Basic Neurochemistry, Eighth Edition, is the updated version of the outstanding and comprehensive classic text on neurochemistry. For more than forty years, this text has been the worldwide standard for information on the biochemistry of the nervous system, serving as a resource for postgraduate trainees and teachers in neurology, psychiatry, and basic neuroscience, as well as for medical, graduate, and postgraduate students and instructors in the neurosciences.
The text has evolved, as intended, with the science. This new edition continues to cover the basics of neurochemistry as in the earlier editions, along with expanded and additional coverage of new research from intracellular trafficking, stem cells, adult neurogenesis, regeneration, and lipid messengers. It contains expanded coverage of all major neurodegenerative and psychiatric disorders, including the neurochemistry of addiction, pain, and hearing and balance; the neurobiology of learning and memory; sleep; myelin structure, development, and disease; autism; and neuroimmunology.
- Completely updated text with new authors and material, and many entirely new chapters
- Over 400 fully revised figures in splendid color
- 61 chapters covering the range of cellular, molecular and medical neuroscience
- Translational science boxes emphasizing the connections between basic and clinical neuroscience
- Companion website at http://elsevierdirect.com/companions/9780123749475
Inhaltsverzeichnis1;Front Cover;1 2;Basic Neurochemistry: Principles of Molecular, Cellular and Medical Neurobiology;4 3;Copyright Page;5 4;Contents;8 5;List of Boxes;10 6;Sections;14 7;Contributors;16 8;Eighth Edition Acknowledgments and History;22 9;Preface to the Eighth Edition;24 10;I. CELLULAR NEUROCHEMISTRY AND NEURAL MEMBRANES;26 10.1;1. Cell Biology of the Nervous System;28 10.1.1;Overview;29 10.1.2;Cellular Neuroscience is the Foundation of Modern Neuroscience;29 10.1.2.1;Diverse cell types comprising the nervous system interact to create a functioning brain;29 10.1.3;Neurons: Common Elements and Diversity;29 10.1.3.1;The classic image of a neuron includes a perikaryon, multiple dendrites and an axon;29 10.1.3.2;Although neurons share common elements with other cells, each component has specialized features;31 10.1.3.3;The axon compartment comprises the axon hillock, initial segment, shaft and terminal arbor;34 10.1.3.4;Dendrites are the afferent components of neurons;34 10.1.3.5;The synapse is a specialized junctional complex by which axons and dendrites emerging from different neurons intercommunicate;35 10.1.4;Macroglia: More than Meets the Eye;36 10.1.4.1;Virtually nothing can enter or leave the central nervous system parenchyma without passing through an astrocytic interphase;36 10.1.4.2;Oligodendrocytes are myelin-producing cells in the central nervous system;38 10.1.4.3;The schwann cell is the myelin-producing cell of the peripheral nervous system;38 10.1.5;Microglia;40 10.1.5.1;The microglial cell plays a role in phagocytosis and inflammatory responses;40 10.1.5.2;Ependymal cells line the brain ventricles and the spinal cord central canal;41 10.1.6;BloodBrain Barriers and the Nervous System;41 10.1.6.1;Homeostasis of the central nervous system (CNS) is vital to the preservation of neuronal function;41 10.1.6.2;The BBB and BCSFB serve a number of key functions critical for brain function;42 10.1.6.3;Evolution of the bloodbrain barrier concept;43 10.1.7;The Neurovascul
ar Unit Includes Multiple Components;43 10.1.7.1;The lumen of the cerebral capillaries that penetrate and course through the brain tissue are enclosed by BECs interconnected by TJ;43 10.1.7.2;The basement membrane (BM)/basal lamina is a vital component of the BBB;44 10.1.7.3;Astrocytes contribute to the maintenance of the BBB;44 10.1.7.4;Pericytes at the BBB are more prevalent than in other capillary types;44 10.1.7.5;Brain endothelial cells restrict the transport of many substances while permitting essential molecules access to the brain;44 10.1.7.6;There are multiple transporters and transport processes for bidirectional transport at the BBB;46 10.1.7.7;Lipid solubility is a key factor in determining the permeability of a substance through the BBB by passive diffusion;46 10.1.7.8;The BBB expresses solute carriers to allow access to the brain of molecules essential for metabolism;47 10.1.7.9;Receptor-mediated transcytosis (RMT) is the primary route of transport for some essential peptides and signaling molecules;47 10.1.7.10;ATP-binding cassette transporters (ABC) on luminal membranes of the BBB restrict brain entry of many molecules;47 10.1.7.11;During development, immune-competent microglia develop and reside in the brain tissue;48 10.1.7.12;There is increasing evidence of BBB dysfunction, either as a cause or consequence, in the pathogenesis of many diseases affecting the CNS;48 10.1.7.13;The presence of an intact BBB affects the success of potentially beneficial therapies for many CNS disorders;48 10.1.8;Acknowledgements;48 10.1.9;References;50 10.2;2. Cell Membrane Structures and Functions;51 10.2.1;Phospholipid Bilayers;51 10.2.1.1;Cells are bounded by proteins arrayed in lipid bilayers;51 10.2.1.2;Amphipathic molecules can form bilayered lamellar structures spontaneously if they have an appropriate geometry;52 10.2.2;Membrane Proteins;53 10.2.2.1;Membrane integral proteins have transmembrane domains that insert directly into lipid bilayers;53 10.2.2.2;Many t
ransmembrane proteins that mediate intracellular signaling form complexes with both intra- and extracellular proteins;54 10.2.2.3;Membrane associations can occur by selective protein binding to lipid head groups;54 10.2.3;Biological Membranes;54 10.2.3.1;The fluidity of lipid bilayers permits dynamic interactions among membrane proteins;54 10.2.3.2;The lipid compositions of plasma membranes, endoplasmic reticulum and golgi membranes are distinct;56 10.2.3.3;Cholesterol transport and regulation in the central nervous system is isolated from that of peripheral tissues;56 10.2.3.4;In adult brain most cholesterol synthesis occurs in astrocytes;56 10.2.3.5;The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling;57 10.2.3.6;The structure and roles of membrane microdomains (lipid rafts) in cell membranes are under intensive study but many aspects are still unresolved;58 10.2.3.7;Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton;59 10.2.3.8;The spectrinankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membrane;59 10.2.3.9;Interaction of rafts with the cytoskeleton is suggested by the results of video microscopy;60 10.2.4;References;63 10.3;3. Membrane Transport;65 10.3.1;Introduction;66 10.3.2;Primary Active Transport (P-Type) Pumps;66 10.3.3;Na,K-Adenosinetriphosphatase (Na,K-ATPase);67 10.3.3.1;The reaction mechanism of Na,K-ATPase illustrates the mechanism of P-type pumps;67 10.3.3.2;Molecular structures of the catalytic subunits in the P-type transporters are similar;68 10.3.3.3;The active Na,K-ATPase is a heterodimer consisting of a catalytic a subunit and an accessory ß subunit;68 10.3.3.4;The a-subunit isoforms are expressed in a cell- and tissue-specific manner;68 10.3.3.5;The ß subunits are monotopic glycoproteins and exhibit some characteristics of cell adhesion molecules;68 10.3.3.6;The Na pump has associated . su
bunits;69 10.3.3.7;A major fraction of cerebral energy production is consumed by the Na,K pump;70 10.3.3.8;Na,K-ATPase Expression patterns change with development, aging and dementia;70 10.3.3.9;Na,K pump content in plasmalemma is regulated by its rapid endocyticexocytic cycling;70 10.3.3.10;The distributions of a-subunit isoforms provide clues to their different physiological functions;70 10.3.3.11;Regulatory factors direct the trafficking of Na,K-ATPase during its synthesis;71 10.3.3.12;The Na,K-ATPase/Src complex functions as a signal receptor for cardiotonic steroids (CTS);71 10.3.3.13;Domain-specific interactions make the Na,K-ATPase an important scaffold in forming signaling microdomains;73 10.3.4;Ca Adenosinetriphosphatases and Na,Ca Antiporters;73 10.3.5;The Primary Plasma Membrane Ca Transporter (PMCA);73 10.3.5.1;PMCA is a plasmalemma P-type pump with high affinity for Ca2+;73 10.3.6;Smooth Endoplasmic Reticulum Calcium Pumps (SERCA);73 10.3.6.1;SERCA, another P-type Ca pump, was first identified in sarcoplasmic reticulum;73 10.3.6.2;High-resolution structural data exist for the SERCA1a Ca pump;73 10.3.7;Other P-Type Transporters;75 10.3.7.1;P-type copper transporters are important for neural function;75 10.3.8;V0V1 Proton Pumps;75 10.3.8.1;The V0V1-ATPase pumps protons into golgi-derived organelles;75 10.3.9;ATP-Binding Cassettes;75 10.3.9.1;The ABC transporters are products of one of the largest known gene superfamilies;75 10.3.9.2;The Three-dimensional structures of several ABC transporters from prokaryotes have been determined;75 10.3.9.3;ABCA1 translocates cholesterol and phospholipids outward across the plasma membrane;76 10.3.9.4;The multidrug-resistance proteins (MDR) can flip amphipathic molecules;77 10.3.10;Secondary Active Transport;77 10.3.10.1;Brain capillary endothelial cells and some neurons express a Na-dependent D-glucose symporter;77 10.3.10.2;Neurotransmitter sodium symporters (NSS) effect the recovery of neurotransmitters from synaptic
clefts;77 10.3.10.3;There are two distinct subfamilies of neurotransmitter sodium symporters;77 10.3.10.4;The SLC6 subfamily of symporters for amino acid transmitters and biogenic amines is characterized by a number of shared structural features;77 10.3.10.5;SLC1 proteins encompass glutamate symporters as well as some amino- and carboxylic-acid transporters expressed in bacteria;78 10.3.10.6;The glutamate symporters in brain are coded by five different but closely related genes, SLC1A14 and SLC1A6;78 10.3.10.7;Failure of regulation of glutamate concentration in its synaptic, extracellular and cytosol compartments leads to critical pathology;79 10.3.10.8;Choline transporter: termination of the synaptic action of acetylcholine is unique among neurotransmitters;79 10.3.10.9;Packaging neurotransmitters into presynaptic vesicles is mediated by proton-coupled antiporters;79 10.3.11;General Physiology of Neurotransmitter Uptake and Storage;80 10.3.12;The Cation Antiporters;80 10.3.12.1;Na,Ca exchangers are important for rapidly lowering high pulses of cytoplasmic Ca2+;80 10.3.12.2;Na,K-ATPase a subunits are coordinated with Na,Ca antiporters and Ca pumps;80 10.3.12.3;The overall mechanism for regulation of cytosolic Ca2+ is complex;80 10.3.13;The Anion Antiporters;81 10.3.13.1;Anion antiporters comprising the SLC8 gene family all transport bicarbonate;81 10.3.13.2;Intracellular pH in brain is regulated by Na,H antiporters, anion antiporters and Na,HCO3 symporters;81 10.3.14;Facilitated Diffusion: Aquaporins and Diffusion of Water;81 10.3.14.1;Simple diffusion of polar water molecules through hydrophobic lipid bilayers is slow;81 10.3.14.2;Crystallographic and architectural data are available for AQP1 and AQP4;82 10.3.14.3;The aquaporins found in brain are AQP1, 4 and 9;82 10.3.14.4;In astrocytic perivascular endfeet membranes, AQP4 is anchored to the dystrophin complex of proteins;82 10.3.14.5;AQP4 exists in astrocyte membranes and is coordinated with other proteins with w
hich its function is integrated;82 10.3.14.6;Rapid diffusion of K+ and H2O from Neuronal extracellular space by astroglia is critical to brain function;83 10.3.14.7;Short-term regulation of AQP4 may result from phosphorylation of either of two serine residues;83 10.3.15;Facilitated Diffusion of Glucose and Myoinositol;83 10.3.15.1;Facilitated diffusion of glucose across the bloodbrain barrier is catalyzed by GLUT-1, -2 and -3;83 10.3.15.2;HMIT is an H-coupled myoinositol symporter;84 10.3.16;References;85 10.4;4. Electrical Excitability and Ion Channels;88 10.4.1;Membrane Potentials and Electrical Signals in Excitable Cells;89 10.4.1.1;Excitable cells have a negative membrane potential;89 10.4.1.2;Real cells are not at equilibrium;90 10.4.1.3;Transport systems may also produce membrane potentials;90 10.4.1.4;Electrical signals recorded from cells are of two types: stereotyped action potentials and a variety of slow potentials;90 10.4.2;Action Potentials in Electrically Excitable Cells;91 10.4.2.1;During excitation, ion channels open and close and a few ions flow;91 10.4.2.2;Gating mechanisms for Na+ and K+ channels in the axolemma are voltage dependent;91 10.4.2.3;The action potential is propagated by local spread of depolarization;92 10.4.2.4;Membranes at nodes of ranvier have high concentrations of Na+ channels;92 10.4.3;Functional Properties of Voltage-Gated Ion Channels;92 10.4.3.1;Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane;92 10.4.3.2;Voltage-dependent gating requires voltage-dependent conformational changes in the protein component(s) of ion channels;93 10.4.3.3;Pharmacological agents acting on ion channels help define their functions;93 10.4.4;The Voltage-Gated Ion Channel Superfamily;94 10.4.4.1;Na+ channels were identified by neurotoxin labeling and their primary structures were established by cDNA cloning;94 10.4.4.2;Ca2+ channels have a structure similar to Na+ channels;96 10.4.4.3;Voltage-gated K+ channels wer
e identified by genetic means;96 10.4.4.4;Inwardly rectifying K+ channels were cloned by expression methods;96 10.4.5;The Molecular Basis for Ion Channel Function;96 10.4.5.1;Much is known about the structural determinants of the ion selectivity filter and pore;96 10.4.5.2;Voltage-dependent activation requires moving charges;99 10.4.5.3;The fast inactivation gate is on the inside;99 10.4.6;Ion Channel Diversity;100 10.4.6.1;Na+ channels are primarily a single family;100 10.4.6.2;Three subfamilies of Ca2+ channels serve distinct functions;100 10.4.6.3;There are many families of K+ channels;101 10.4.6.4;More ion channels are related to the NaV, CaV and KV families;101 10.4.6.5;There are many other kinds of ion channels with different structural backbones and topologies;102 10.4.6.6;Ion channels are the targets for mutations that cause genetic diseases;102 10.4.7;Acknowledgments;102 10.4.8;References;104 10.5;5. Lipids;106 10.5.1;Introduction;106 10.5.2;Properties of Brain Lipids;107 10.5.2.1;Lipids have multiple functions in brain;107 10.5.2.2;Membrane lipids are amphipathic molecules;107 10.5.2.3;The hydrophobic components of many lipids consist of either isoprenoids or fatty acids and their derivatives;107 10.5.2.4;Isoprenoids have the unit structure of a five-carbon branched chain;107 10.5.2.5;Brain fatty acids are long-chain carboxylic acids that may contain one or more double bonds;107 10.5.3;Complex Lipids;108 10.5.3.1;Glycerolipids are derivatives of glycerol and fatty acids;108 10.5.3.2;In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone;110 10.5.4;Analysis of Brain Lipids;114 10.5.4.1;Chromatography and mass spectrometry are employed to analyze and classify brain lipids;114 10.5.5;Brain Lipid Biosynthesis;115 10.5.5.1;Acetyl coenzyme A is the precursor of both cholesterol and fatty acids;115 10.5.5.2;Phosphatidic acid is the precursor of all glycerolipids;119 10.5.5.3;Sphingolipids are biosynthesized by adding head groups to th
e ceramide moiety;121 10.5.6;Genes for Enzymes Catalyzing Synthesis and Degradation of Lipids;121 10.5.7;Lipids in the Cellular Milieu;123 10.5.7.1;Lipids are transported between membranes;123 10.5.7.2;Membrane lipids may be asymmetrically oriented;123 10.5.7.3;Some proteins are bound to membranes by covalently linked lipids;123 10.5.7.4;Lipids have multiple roles in cells;124 10.5.8;Summary;124 10.5.9;Acknowledgments;124 10.5.10;References;124 10.6;6. The Cytoskeleton of Neurons and Glia;126 10.6.1;Introduction;126 10.6.2;Molecular Components of the Neuronal Cytoskeleton;127 10.6.2.1;Along with the nucleus and mitochondria, the cytoskeleton is one of several biological structures that define eukaryotic cells;127 10.6.2.2;Microtubules act as both dynamic structural elements and tracks for organelle traffic;127 10.6.2.3;Neuronal and glial intermediate filaments provide support for neuronal and glial morphologies;131 10.6.2.4;Actin microfilaments and the membrane cytoskeleton play critical roles in neuronal growth and secretion;133 10.6.3;Ultrastructure and Molecular Organization of Neurons and Glia;135 10.6.3.1;A dynamic neuronal cytoskeleton provides for specialized functions in different regions of the neuron;135 10.6.3.2;Both the composition and organization of cytoskeletal elements in axons and dendrites become specialized early in differentiation;136 10.6.4;Cytoskeletal Structures in the Neuron Have Complementary Distributions and Functions;137 10.6.4.1;Microfilament and microtubule dynamics underlie growth cone motility and function;137 10.6.4.2;The axonal cytoskeleton may be influenced by glia;137 10.6.4.3;Levels of cytoskeletal protein expression change after injury and during regeneration;139 10.6.4.4;Alterations in the cytoskeleton are frequent hallmarks of neuropathology;139 10.6.4.5;Phosphorylation of cytoskeletal proteins is involved both in normal function and in neuropathology;141 10.6.5;Summary;141 10.6.6;References;141 10.7;7. Intracellular Trafficki
ng;144 10.7.1;Introduction;145 10.7.2;General Mechanisms of Intracellular Membrane Trafficking in Mammalian Cells Include Both Universal and Highly Specialized Processes;145 10.7.3;Fundamentals of Membrane Trafficking are Based on a set of Common Principles;146 10.7.3.1;Most transport vesicles bud off as coated vesicles, with a unique set of proteins decorating their cytosolic surface;146 10.7.3.2;GTP-binding proteins, such as small monomeric GTPases and heterotrimeric GTPases (G proteins) facilitate membrane transport;147 10.7.3.3;Dynamins are involved in pinching off of many vesicles and membrane-bounded organelles;148 10.7.3.4;Removal of coat proteins is catalyzed by specific protein chaperones;149 10.7.3.5;SNARE proteins and rabs control recognition of specific target membranes;150 10.7.3.6;Unloading of the transport vesicle cargo to the target membrane occurs by membrane fusion;150 10.7.4;The biosynthetic Secretory Pathway Includes Synthetic, Processing, Targeting and Secretory Steps;151 10.7.4.1;Historically, endoplasmic reticulum has been classified as rough or smooth, based on the presence (RER) or absence (SER) of membraneassociated polysomes;151 10.7.4.2;Biosynthetic and secretory cargo leaving the ER is packaged in COPII-coated vesicles for delivery to the Golgi complex;152 10.7.4.3;The Golgi apparatus is a highly polarized organelle consisting of a series of flattened cisternae, usually located near the nucleus and the centrosome;154 10.7.4.4;Processing of proteins in the Golgi complex includes sorting and glycosylation of membrane proteins and secretory proteins;154 10.7.4.5;Proteins and lipids move through Golgi cisternae from the cis to the trans direction;155 10.7.4.6;Plasma membrane proteins are sorted to their final destinations at the trans-Golgi network;156 10.7.4.7;Lysosomal proteins are also sorted and targeted in the trans-Golgi network;157 10.7.4.8;Several intracellular trafficking pathways converge at lysosomes;157 10.7.4.9;Both constitutive
and regulated neuroendocrine secretion pathways exist in cells of the nervous system;157 10.7.4.10;The constitutive secretory pathway is also known as the default pathway because it occurs in the absence of a triggering signal;159 10.7.4.11;Secretory cells, including neurons, possess a specialized regulated secretory pathway;159 10.7.4.12;Secretory vesicle biogenesis requires completion of a characteristic sequence of steps before vesicles are competent for secretion;159 10.7.5;The Endocytic Pathway Plays Multiple Roles in Cells of the Nervous System;160 10.7.5.1;Endocytosis for degradation of macromolecules and uptake of nutrients involves phagocytosis, pinocytosis and autophagy;160 10.7.5.2;Retrieval of membrane components in the secretory pathway through receptor-mediated endocytosis (RME) is a clathrin-coat-dependent process;162 10.7.6;Synaptic Vesicle Trafficking is a Specialized Form of Regulated Secretion and Recycling Optimized for Speed and Efficiency;164 10.7.6.1;The organization of the presynaptic terminal is one important element for optimization of secretion and recycling;164 10.7.6.2;In a simplistic model, the exocytosis step of neurotransmission takes place in at least three major different steps;164 10.7.6.3;Many years have passed since the concept of synaptic vesicle recycling was introduced in the early 1970s, but details;167 10.7.7;Acknowledgments;169 10.7.8;References;169 10.8;8. Axonal Transport;171 10.8.1;Introduction;171 10.8.2;Neuronal Organelles in Motion;172 10.8.3;Discovery and Development of the Concept of Fast and Slow Components of Axonal Transport;172 10.8.3.1;The size and extent of many neurons presents a special set of challenges;172 10.8.3.2;Fast and slow components of axonal transport differ in both their constituents and their rates;173 10.8.3.3;Features of fast axonal transport demonstrated by biochemical and pharmacological approaches are apparent from video images;176 10.8.4;Fast Axonal Transport;176 10.8.4.1;Newly synthesized
membrane and secretory proteins destined for the axon travel by fast anterograde transport;176 10.8.4.2;Passage through the golgi apparatus is obligatory for most proteins destined for fast axonal transport;177 10.8.4.3;Anterograde fast axonal transport moves synaptic vesicles, axolemmal precursors, and mitochondria down the axon;178 10.8.4.4;Retrograde transport returns trophic factors, exogenous material, and old membrane constituents to the cell body;178 10.8.4.5;Molecular sorting mechanisms ensure delivery of proteins to discrete membrane compartments;179 10.8.5;Slow Axonal Transport;180 10.8.5.1;Cytoplasmic and cytoskeletal elements move coherently at slow transport rates;180 10.8.5.2;Axonal growth and regeneration are limited by rates of slow axonal transport;180 10.8.5.3;Properties of slow axonal transport suggest molecular mechanisms;181 10.8.6;Molecular Motors: Kinesin, Dynein and Myosin;181 10.8.6.1;The characteristic biochemical properties of different molecular motors aided in their identification;182 10.8.6.2;Kinesins mediate anterograde fast axonal transport in a variety of cell types;182 10.8.6.3;Mechanisms underlying attachment of motors to transported MBOs remain elusive;183 10.8.6.4;Multiple members of the kinesin superfamily are expressed in the nervous system;183 10.8.6.5;Cytoplasmic dyneins have multiple roles in the neuron;184 10.8.6.6;Different classes of myosin are important for neuronal function;185 10.8.6.7;Matching motors to physiological functions may be difficult;185 10.8.7;AXONAL Transport and Neuropathology;186 10.8.8;Acknowledgments;187 10.8.9;References;187 10.9;9. Cell Adhesion Molecules;190 10.9.1;Overview;190 10.9.1.1;Cell adhesion molecules comprise several superfamilies;191 10.9.2;Immunoglobulin Superfamily;191 10.9.2.1;The immunoglobulin (Ig)-like domain is a typical feature of proteins belonging to the immunoglobulin superfamily;191 10.9.2.2;Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) represent a divers
e group of proteins;191 10.9.2.3;IgCAMs signal to the cytoplasm;193 10.9.3;Cadherins;194 10.9.3.1;The extracellular cadherin (EC) repeat is a typical feature of cadherins;194 10.9.3.2;The type I (classic) cadherins are homophilic cell adhesion molecules;194 10.9.3.3;Cadherins are involved in multiple processes in the nervous system;194 10.9.4;Integrins;195 10.9.4.1;Integrins are the major cell surface receptors responsible for cell adhesion to extracellular matrix (ECM) proteins;195 10.9.4.2;Integrins signal in an inside-out and outside-in fashion;197 10.9.4.3;Integrins regulate myelination;198 10.9.5;Cooperation and Crosstalk between Cell Adhesion Molecules;200 10.9.5.1;Various cell adhesion molecules cooperatively regulate the formation of interneuronal synapses in the CNS;200 10.9.5.2;Integrin-cadherin cross-talk regulates neurite outgrowth;202 10.9.6;Summary;203 10.9.7;References;203 10.10;10. Myelin Structure and Biochemistry;205 10.10.1;The Myelin Sheath;205 10.10.1.1;Myelin facilitates conduction;205 10.10.1.2;Myelin has a characteristic ultrastructure;206 10.10.1.2.1;Nodes of Ranvier;207 10.10.1.3;Myelin is an extension of a cell membrane;209 10.10.1.4;Myelin affects axonal structure;210 10.10.2;Characteristic Composition of Myelin;210 10.10.2.1;The composition of myelin is well characterized because it can be isolated in high yield and purity by subcellular fractionation;210 10.10.2.2;Central nervous system myelin is enriched in certain lipids;211 10.10.2.3;Peripheral and central nervous system myelin lipids are qualitatively similar;212 10.10.2.4;Central nervous system myelin contains some unique proteins;213 10.10.2.4.1;Proteolipid protein;213 10.10.2.4.2;Myelin basic proteins;214 10.10.2.4.3;2':3'-cyclic nucleotide 3'-phosphodiesterase;215 10.10.2.4.4;Myelin-associated glycoprotein (MAG) and other glycoproteins of CNS myelin;216 10.10.2.5;Peripheral myelin also contains unique proteins;217 10.10.2.5.1;P0 glycoprotein;217 10.10.2.5.2;Peripheral myelin pro
tein-22;217 10.10.2.5.3;P2 protein;218 10.10.2.6;Some classically defined myelin proteins are common to both CNS and PNS myelin;218 10.10.2.6.1;Myelin basic protein;218 10.10.2.6.2;Myelin-associated glycoprotein;218 10.10.2.7;Myelin sheaths contain other proteins, some of which have only recently been established as myelin related;219 10.10.2.7.1;Tetraspan proteins;219 10.10.2.7.2;Nodal, paranodal, and juxtaparanodal proteins;220 10.10.2.7.3;Enzymes associated with myelin;220 10.10.2.7.4;Neurotransmitter receptors associated with myelin;222 10.10.2.7.5;Other myelin-related proteins;222 10.10.3;Acknowledgments;222 10.10.4;References;222 10.11;11. Energy Metabolism of the Brain;225 10.11.1;Introduction;226 10.11.1.1;Processes related to signaling require a larger proportion of energy than do basic cellular functions;226 10.11.1.2;Function-derived signals arising from metabolism are used for brain imaging;227 10.11.1.3;Major cell types and their subcellular structures have different energetic requirements and metabolic capabilities;228 10.11.2;Substrates for Cerebral Energy Metabolism;228 10.11.2.1;Energy-yielding substrates enter the brain from the blood through the bloodbrain barrier;228 10.11.2.2;Endothelial cells of the bloodbrain barrier and brain cells have specific transporters for the uptake of glucose and monocarboxylic acids;228 10.11.2.3;Bloodbrain barrier transport can be altered under pathological conditions;229 10.11.3;Age and Development Influence Cerebral Energy Metabolism;229 10.11.3.1;The transporters and pathways of metabolism change during development;229 10.11.3.2;Cerebral metabolic rate increases during early development;230 10.11.3.3;Cerebral metabolic rate declines from developmental levels and plateaus after maturation;230 10.11.4;Fueling Brain: SupplyDemand Relationships and Cerebral Metabolic Rate;230 10.11.4.1;Both excitatory and inhibitory neuronal signals utilize energy derived from metabolism;230 10.11.4.2;Continuous cerebral circulation
is required to sustain brain function;231 10.11.4.3;Glucose is the main obligatory substrate for energy metabolism in adult brain;231 10.11.5;Metabolism in the Brain is Highly Compartmentalized;232 10.11.5.1;Glucose has numerous metabolic fates in brain;232 10.11.6;Glycolysis: Conversion of Glucose to Pyruvate;232 10.11.6.1;Regulation of brain hexokinase;232 10.11.6.2;Phosphofructokinase is the major regulator of brain glycolysis;233 10.11.6.3;Glycolysis produces ATP, pyruvate for mitochondrial metabolism, and precursors for amino acids and complex carbohydrates;233 10.11.7;Glycogen is Actively Synthesized and Degraded in Astrocytes;234 10.11.7.1;The steady-state concentration of glycogen is regulated by coordination of separate degradative and synthetic enzymatic processes;235 10.11.8;The Pentose Phosphate Shunt has Essential Roles in Brain;235 10.11.9;The MalateAspartate Shuttle has a key Role in Brain Metabolism;235 10.11.9.1;The malateaspartate shuttle is the most important pathway for transferring reducing equivalents from the cytosol to the;235 10.11.9.2;The malateaspartate shuttle has a role in linking metabolic pathways in brain;236 10.11.10;There is Active Metabolism of Lactate in Brain;236 10.11.10.1;Lactatepyruvate interconversion;236 10.11.10.2;Lactate is formed in brain under many conditions;236 10.11.10.3;Compartmentation of the pyruvatelactate pool is unexpectedly complex;239 10.11.10.4;Lactate can serve as fuel for brain cells under various conditions;239 10.11.10.5;The astrocyteneuron lactate shuttle is controversial;240 10.11.11;Major Functions of the Tricarboxylic Acid (TCA) Cycle: Pyruvate Oxidation to CO2, NADH/FADH2 Formation for ATP Generation;240 10.11.11.1;The TCA (citric acid) cycle is multifunctional;240 10.11.11.2;The pyruvate dehydrogenase complex plays a key role in regulating oxidation of glucose;242 10.11.11.3;TCA cycle rate;242 10.11.11.4;Malate dehydrogenase is one of several enzymes in the TCA cycle present in both the cytoplasm an
d mitochondria;242 10.11.11.5;The electron transport chain produces ATP;242 10.11.11.6;ATP production in brain is highly regulated;242 10.11.11.7;Phosphocreatine has a role in maintaining ATP levels in brain;243 10.11.11.8;Pyruvate carboxylation in astrocytes is the major anaplerotic pathway in brain;243 10.11.11.9;Citrate is a multifunctional compound predominantly synthesized and released by astrocytes;243 10.11.11.10;Acetyl-coenzyme A formed from glucose is the precursor for acetylcholine in neurons;243 10.11.12;Mitochondrial Heterogeneity: Differential Distribution of Many TCA Cycle Enzymes and Components of Oxidative Phosphorylation;244 10.11.12.1;Mitochondria are distributed with varying densities throughout the central nervous system, with the more vascular parts;244 10.11.12.2;Mitochondrial heterogeneity leads to multiple simultaneous TCA cycles in astrocytes and neurons;244 10.11.12.3;Partial TCA cycles can provide energy in brain;244 10.11.12.4;Other substrates (e.g., glutamate, glutamine, lactate, fatty acids, and ketone bodies) can provide energy for brain cells;244 10.11.13;GlutamateGlutamine Metabolism is Linked to Energy Metabolism;245 10.11.13.1;Transporters are required to carry glutamate and other amino acids across the mitochondrial membrane;245 10.11.13.2;Metabolism of both glutamate and glutamine is linked to TCA cycle activity;245 10.11.13.3;Glutamate participates in a number of metabolic pathways, and metabolism of glutamate and glutamine is compartmentalized;245 10.11.13.3.1;The glutamateglutamine cycle;246 10.11.13.4;A specialized glutamateglutamine cycle operates in Gabaergic neurons and surrounding astrocytes;247 10.11.13.5;Several shuttles act to transfer nitrogen in brain;247 10.11.14;Metabolic Studies in Brain: Imaging and Spectroscopy;247 10.11.14.1;Global assays of whole brain;247 10.11.14.2;Local rates of glucose and oxygen utilization, functional brain imaging, redox state, and metabolic pathway analysis;247 10.11.14.3;Carbon-13 nuc
lear magnetic resonance spectroscopy (NMR or MRS) for studying brain metabolism;249 10.11.14.4;Cultured neurons and astrocytes are useful for studying subcellular compartmentation and identifying pathways of metabolism;250 10.11.14.5;Metabolic assays in brain slices, axons, synaptosomes and isolated mitochondria;251 10.11.14.6;Concentrations of compounds in brain and regulation of metabolism in the intact brain;251 10.11.15;Relation of Energy Metabolism to Pathological Conditions in the Brain;251 10.11.16;Acknowledgments;251 10.11.17;References;251 11;II. INTERCELLULAR SIGNALING;258 11.1;12. Synaptic Transmission and Cellular Signaling: An Overview;260 11.1.1;Synaptic Transmission;260 220.127.116.11;Chemical transmission between nerve cells involves multiple steps;260 18.104.22.168;Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells;262 22.214.171.124;A variety of methods have been developed to study exocytosis;263 126.96.36.199;The neuromuscular junction is a well-defined structure that mediates the release and postsynaptic effects of acetylcholine;263 188.8.131.52;Quantal analysis defines the mechanism of release as exocytosis;264 184.108.40.206;Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis;264 220.127.116.11;Presynaptic events during synaptic transmission are rapid, dynamic and interconnected;266 18.104.22.168;Because fast synaptic transmission involves recycling vesicles, the neurotransmitter must be replenished locally;270 22.214.171.124;Discrete steps in the regulated secretory pathway can be defined in neuroendocrine cells;270 11.1.2;Cellular Signaling Mechanisms;270 126.96.36.199;Background;270 188.8.131.52;Three phases of receptor-mediated signaling can be identified;271 184.108.40.206;Several major molecular mechanisms that link agonist occupancy of cell-surface receptors to functional responses have been identified;271 220.127.116.11.1;First group;271 18.104.22.168.2;Second group;2
73 22.214.171.124.3;Third group;273 126.96.36.199.4;Fourth group;273 188.8.131.52;Cross-talk can occur between intracellular signaling pathways;274 184.108.40.206;Signaling molecules can activate gene transcription;274 220.127.116.11;Nitric oxide acts as an intercellular signaling molecule in the central nervous system;274 18.104.22.168;Astrocytes also play a pivotal role in signaling events at the synapse;281 11.1.3;Acknowledgments;281 11.1.4;References;281 11.2;13. Acetylcholine;283 11.2.1;Introduction;284 11.2.2;Synthesis, Storage and Release of Acetylcholine: Distribution of Cholinergic Pathways;285 22.214.171.124;Acetylcholine formation is catalyzed by choline acetyltransferase;285 126.96.36.199;Choline is accumulated into synaptic terminals via a specific high-affinity transporter;285 188.8.131.52;ACh is packaged into vesicles by a specific transporter and is released from neurons in a Ca2+-dependent manner;286 184.108.40.206;Cholinergic neurons are widely distributed within the CNS;287 11.2.3;Enzymatic Breakdown of Acetylcholine;287 220.127.116.11;Acetylcholinesterase and the removal of ACh;287 18.104.22.168;Molecular forms of AChE;287 22.214.171.124;AChE is encoded by a single gene that is subject to alternative splicing;288 126.96.36.199;AChE catalysis: mechanism of a nearly perfect enzyme;288 188.8.131.52;The active site is at the bottom of a narrow gorge in the AChE protein;289 184.108.40.206;Inhibitors of AChE have toxicological, agrochemical and clinical significance;290 220.127.116.11;Does AChE have other functions?;291 11.2.4;Nicotinic Cholinergic Receptors;291 18.104.22.168;The nicotinic receptor was the first receptor to be characterized biochemically;291 22.214.171.124;nAChRs are pentameric ligand-gated ion channels;292 126.96.36.199;Agonists bind at the interface between adjacent subunits;293 188.8.131.52;The nAChR is the prototypical member of the cys-loop family of ligand-gated ion channel receptors;294 184.108.40.206;The nAChR ion channel;294 220.127.116.11;The prolonged presence of agonist leads to desensitization;294 18.104.22.168;Neuronal nAChRs form a family of rela
ted receptors;294 22.214.171.124;The permutations of subunits forming nAChRs create more diversity;296 126.96.36.199;Neuronal nAChRs modulate brain function;296 188.8.131.52;Transgenic mice help to reveal the physiological roles and clinical implications of nAChRs;296 184.108.40.206;Neuronal nAChRs are also present in non-neuronal cells;297 220.127.116.11;nAChRs and disease;297 18.104.22.168;nAChRs as therapeutic targets;298 11.2.5;Muscarinic Cholinergic Receptors;299 22.214.171.124;Some effects of ACh can be mimicked by the alkaloid muscarine;299 126.96.36.199;Muscarinic cholinergic responses are mediated by G-proteincoupled receptors;299 188.8.131.52;Pharmacological studies were the first to indicate the presence of multiple mAChR subtypes;299 184.108.40.206;Molecular cloning of the mAChR reveals five subtypes;300 220.127.116.11;Muscarinic receptor subtypes couple to distinct G-proteins and activate different effector mechanisms;301 18.104.22.168;Muscarinic receptor subtypes are not uniformly distributed throughout the CNS and are present at different subcellular locations;302 22.214.171.124;Muscarinic receptors in the CNS have been implicated in a number of neuropsychiatric disorders;302 126.96.36.199;Transgenic mice permit an assessment of the physiological roles of individual subtypes in vivo;302 188.8.131.52;Pharmacological therapies are used to treat cholinergic disorders;303 11.2.6;References;305 11.3;14. Catecholamines;308 11.3.1;Overview of Catecholamines;308 184.108.40.206;Catecholamines belong to the group of transmitters called monoamines;308 220.127.116.11;Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis;309 18.104.22.168;Aromatic amino acid decarboxylase (AAAD), also called DOPA decarboxylase, catalyzes the conversion of L-DOPA to dopamine;310 22.214.171.124;In noradrenergic and adrenergic neurons, dopamine is further converted to norepinephrine by Dopamine-ß-hydroxylase (DBH);311 126.96.36.199;In select neurons and adrenal medulla, norepinephrine is metabolized to epinephrine by phenylethanolamine-n-methyltransferase (PNM
T);313 188.8.131.52;Catecholamines are stored in small, clear synaptic vesicles or large, dense-core granules;313 184.108.40.206;Catecholamines are released from synaptic vesicles and the vesicles recycle;313 220.127.116.11;The physiological actions of catecholamines are terminated by reuptake into the neuron, catabolism and diffusion;313 18.104.22.168;Diffusion also plays an important role in the inactivation of catecholamines;315 22.214.171.124;Catecholamines are primarily metabolized by monoamine oxidase and catechol-o-methyltransferase;315 126.96.36.199.1;Monoamine oxidase (MAO);315 188.8.131.52.2;Catechol-O-methyltransferase (COMT);316 184.108.40.206.3;Dopamine metabolites;317 220.127.116.11.4;Norepinephrine metabolism;317 11.3.2;Neuroanatomy;317 18.104.22.168;Catecholamines elicit their effects by binding to cell-surface receptors;318 11.3.3;Adrenergic Receptors;320 22.214.171.124;All adrenergic receptors are GPCRs;320 11.3.4;Agonist-Induced Downregulation;322 11.3.5;Repeated Antagonist Treatment;322 11.3.6;References;323 11.4;15. Serotonin;325 11.4.1;Serotonin, the Neurotransmitter;326 126.96.36.199;The indolealkylamine 5-hydroxytryptamine (5-HT; serotonin) was initially identified because of its effects on smooth muscle;326 188.8.131.52;Understanding the neuroanatomical organization of serotonergic neurons provides insight into the functions of this neurotransmitter;326 184.108.40.206;The amino acid L-tryptophan serves as the precursor for the synthesis of 5-HT;329 220.127.116.11;The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter;331 18.104.22.168;As with other biogenic amine transmitters, 5-HT is stored primarily in vesicles and is released by an exocytotic mechanism;331 22.214.171.124;The activity of 5-HT in the synapse is terminated primarily by its reuptake into serotonergic terminals;333 126.96.36.199;Acute and chronic regulation of SERT function provides mechanisms for altering synaptic 5-HT concentrations and neurotransmission;334 188.8.131.52;The primary catabolic pathway for 5-HT is oxidative deaminat
ion by the enzyme monoamine oxidase;335 184.108.40.206;In addition to classical synaptic transmission, 5-HT may relay information by volume transmission or paracrine neurotransmission;336 220.127.116.11;5-HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state;336 18.104.22.168;5-HT modulates neuroendocrine function;337 22.214.171.124;5-HT modulates circadian rhythmicity;337 126.96.36.199;5-HT modulates feeding behavior and food intake;337 11.4.2;Serotonin Receptors;338 188.8.131.52;Pharmacological and physiological studies have contributed to the definition of the many receptor subtypes for serotonin;338 184.108.40.206;The application of techniques used in molecular biology to the study of 5-HT receptors led to the rapid discovery of addition;339 220.127.116.11;The 5-HT1 receptor family is composed of the 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-HT1F receptors;339 18.104.22.168.1;The 5-HT1A receptor;339 22.214.171.124.2;The 5-HT1B and 5-HT1D receptor subtypes;341 126.96.36.199.3;The 5-ht1E receptor;342 188.8.131.52.4;The 5-HT1F receptor;342 184.108.40.206;The 5-HT2 receptor family is composed of the 5-HT2A, 5-HT2B and 5HT2C receptors;342 220.127.116.11.1;5-HT2A receptors;342 18.104.22.168.2;The 5-HT2B receptor;343 22.214.171.124.3;The 5-HT2C receptor;343 126.96.36.199;Unlike the other subtypes of receptor for 5-HT, the 5-HT3 receptor is a ligand-gated ion channel;343 188.8.131.52.1;The 5-HT3 receptor;343 184.108.40.206;The 5-HT4, 5-HT6 and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase;344 220.127.116.11.1;The 5-HT4 receptor;344 18.104.22.168.2;The 5-HT6 receptor;345 22.214.171.124.3;The 5-HT7 receptor;345 126.96.36.199;The 5-ht5 receptor and the 5-ht1P receptor are orphan receptors;345 11.4.3;References;346 11.5;16. Histamine;348 11.5.1;Introduction;349 11.5.2;Histamine: The Molecule and the Messenger;349 188.8.131.52;Histamine is a mediator of several physiological and pathological processes within and outside of the nervous system;349 184.108.40.206;The chemical structure of histamine has similarities to the struc
tures of other biogenic amines, but important differences also exist;349 11.5.3;Histaminergic Cells of the Central Nervous System: Anatomy and Morphology;349 220.127.116.11;The brain stores and releases histamine from more than one type of cell;349 18.104.22.168;Several functions for brain and dural mast cells are investigated;349 22.214.171.124;Histaminergic fibers originate from the tuberomamillary (TM) region of the posterior hypothalamus;349 126.96.36.199;Histaminergic neurons have morphological and membrane properties that are similar to those of neurons storing other biogenic amines;350 188.8.131.52;Histaminergic fibers project widely to most regions of the central nervous system;350 11.5.4;Dynamics of Histamine in the Brain;352 184.108.40.206;Specific enzymes control histamine synthesis and breakdown;352 220.127.116.11;Several forms of histidine decarboxylase (HDC) may derive from a single gene;353 18.104.22.168;Histamine synthesis in the brain is controlled by the availability of l-histidine and the activity of HDC;353 22.214.171.124;Histamine is stored within and released from neurons;353 126.96.36.199;In the vertebrate brain, histamine metabolism occurs predominantly by methylation;353 188.8.131.52;Neuronal histamine can be methylated outside of histaminergic nerve terminals;353 184.108.40.206;A polymorphism in human HMT (Thr105Ile) may be an important regulatory factor in some human disorders;354 220.127.116.11;The activity of histaminergic neurons is regulated by H3 autoreceptors and by other transmitter receptors;354 11.5.5;Molecular Sites of Histamine Action;354 18.104.22.168;Histamine acts on four G-proteincoupled receptors (GPCRs), three of which are clearly important in the brain;354 22.214.171.124;H1 receptors are intronless GPCRs linked to Gq and calcium mobilization;354 126.96.36.199.1;H1-linked intracellular messengers;355 188.8.131.52;H2 receptors are intronless GPCRs linked to Gs and cyclic AMP synthesis;356 184.108.40.206.1;H2-linked intracellular messengers;356 220.127.116.11;H3 receptors are a family of GPCRs produced by gene splicing and l
inked to Gi/o;356 18.104.22.168.1;H3 receptor gene splicing;358 22.214.171.124.2;H3-linked intracellular messengers;358 126.96.36.199.3;Constitutive H3 receptor activity;359 188.8.131.52;H4 receptors are very similar to H3 receptors in gene structure and signal transduction, but show limited expression in the brain;359 184.108.40.206.1;H4-linked intracellular messengers;360 220.127.116.11;Histamine can modify ionotropic transmission;360 11.5.6;Histamine Actions on the Nervous System;360 18.104.22.168;Histamine in the brain may act as both a neuromodulator and a classical transmitter;360 22.214.171.124;Histaminergic neurons are mutually connected with other neurotransmitter systems;360 126.96.36.199;Histamine functions in the nervous system;361 188.8.131.52;Histamine may contribute to nervous system diseases or disorders;362 11.5.7;Significance of Brain Histamine for Drug Action;362 184.108.40.206;Many clinically available drugs that modify sleepwake cycles and appetite act through the histaminergic system;362 220.127.116.11;Drugs that modify pain perception act in part through the histaminergic system;362 18.104.22.168;The H3 receptor is an attractive target for the treatment of several CNS diseases;362 11.5.8;References;364 11.6;17. Glutamate and Glutamate Receptors;367 11.6.1;The Amino Acid Glutamate is the Major Excitatory Neurotransmitter in the Brain;368 11.6.2;Brain Glutamate is Derived from Blood-Borne Glucose and Amino Acids that Cross the BloodBrain Barrier;368 11.6.3;Glutamine is an Important Immediate Precursor for Glutamate: The Glutamine Cycle;369 22.214.171.124;Release of glutamate from nerve endings leads to loss of a-ketoglutarate from the tricarboxylic acid cycle;370 11.6.4;Synaptic Vesicles Accumulate Transmitter Glutamate by Vesicular Glutamate Transporters;371 126.96.36.199;Zinc is present together with glutamate in some glutamatergic vesicles;371 11.6.5;Is Aspartate a Neurotransmitter?;371 11.6.6;Long-Term Potentiation or Depression of Glutamatergic Synapses May Underlie Learning;371 11.6.7;The Neuronal Pathways of the Hipp
ocampus are Essential Structures for Memory Formation;372 11.6.8;Ionotropic and Metabotropic Glutamate Receptors are Principal Proteins at the Postsynaptic Density;372 11.6.9;Three Classes of Ionotropic Glutamate Receptors are Identified;372 188.8.131.52;Seven functional families of ionotropic glutamate receptor subunits can be defined by structural homologies;373 184.108.40.206;AMPA and kainate receptors are both blocked by quinoxalinediones but have different desensitization pharmacologies;375 220.127.116.11;N-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites;375 18.104.22.168;The transmembrane topology of glutamate receptors differs from that of nicotinic receptors;379 22.214.171.124;Structure of the agonist-binding site has been analyzed;379 126.96.36.199;Genetic regulation via splice variants and RNA editing further increases receptor heterogeneity: the flip/flop versions;379 188.8.131.52;The permeation pathways of all ionotropic glutamate receptors are similar, but vive la difference;381 11.6.10;Glutamate Produces Excitatory Postsynaptic Potentials;381 184.108.40.206;Genetic knockouts provide clues to ionotropic receptor functions;383 11.6.11;Metabotropic Glutamate Receptors Modulate Synaptic Transmission;383 220.127.116.11;Eight metabotropic glutamate receptors (mGlu receptors) have been identified that embody three functional classes;383 18.104.22.168;mGlu receptors are linked to diverse cytoplasmic signaling enzymes;383 22.214.171.124;Postsynaptic mGlu receptor activation modulates ion channel activity;383 126.96.36.199;Presynaptic mGlu receptor activation can lead to presynaptic inhibition;384 188.8.131.52;Genetic knockouts provide clues to mGlu receptor functions;384 11.6.12;Glutamate Receptors Differ in their Postsynaptic Distribution;384 11.6.13;Proteins of the Postsynaptic Density Mediate Intracellular Effects of Glutamate Receptor Activation;385 184.108.40.206;A major scaffolding protein of the PSD is PSD95;385 220.127.116.11;Small GTP-binding proteins (GTPases) mediate changes in gene expression upon NMD
A receptor activation;386 11.6.14;Dendritic Spines are Motile, Changing their Shape and Size in Response to Synaptic Activity within Minutes;386 11.6.15;Sodium-Dependent Symporters in the Plasma Membranes Clear Glutamate from the Extracellular Space;386 11.6.16;Sodium-Dependent Glutamine Transporters in Plasma Membranes Mediate the Transfer of Glutamine from Astrocytes to Neurons;387 11.6.17;Excessive Glutamate Receptor Activation may Mediate Certain Neurological Disorders;388 18.104.22.168;Glutamate and its analogs can be neurotoxins and cause excitotoxicity;388 22.214.171.124;Some dietary neurotoxins may cause excessive glutamate receptor activation and cell death;388 126.96.36.199;Abnormal activation of glutamate receptors in disorders of the central nervous system;388 11.6.18;References;390 11.7;18. GABA;392 11.7.1;Introduction;392 11.7.2;GABA Synthesis, Release and Uptake;393 188.8.131.52;GABA is formed in vivo by a metabolic pathway referred to as the GABA shunt;393 11.7.3;GABA Receptor Physiology and Pharmacology;393 184.108.40.206;GABA receptors have been identified electrophysiologically and pharmacologically in all regions of the brain;393 11.7.4;Structure and Function of GABA Receptors;394 220.127.116.11;GABAB receptors are coupled to G proteins and a variety of effectors;394 18.104.22.168;GABAB receptors are heterodimers;394 22.214.171.124;GABAA receptors are chloride channels and members of a superfamily of ligand-gated ion channel receptors;395 126.96.36.199;A family of pentameric GABAA-receptor protein subtypes exists; these vary in their localization, and in virtually every pro ...;395 188.8.131.52;The GABAA receptor is the major molecular target for the action of many drugs in the brain;397 184.108.40.206;Neurosteroids, which may be physiological endogenous modulators of brain activity, enhance GABAA receptor function;399 220.127.116.11;The three-dimensional structures of ligand-gated ion channel receptors are being modeled successfully;399 18.104.22.168;Mouse genetics reveal important functions for GABAA receptor
subtypes;400 11.7.5;GABA is the Major Rapidly Acting Inhibitory Neurotransmitter in Brain;400 11.7.6;References;400 11.8;19. Purinergic Signaling;402 11.8.1;Nomenclature of Purines and Pyrimidines;402 11.8.2;Purine Release;402 22.214.171.124;Extracellular nucleotides are regulated by ectoenzymes;404 126.96.36.199;There are several sources of extracellular adenosine;404 11.8.3;Purinergic Receptors;407 188.8.131.52;There are four adenosine receptor subtypes;407 184.108.40.206;Adenosine A1 receptors (A1R);408 220.127.116.11;A2A adenosine receptors are highly expressed in the basal ganglia;408 18.104.22.168;A2B adenosine receptors regulate vascular permeability;409 22.214.171.124;A3 adenosine receptors are few in number in the central nervous system;409 126.96.36.199;P2 receptors are subdivided into ionotropic P2X receptors and metabotropic P2Y receptors;409 11.8.4;Effects of Purines in the Nervous System;409 188.8.131.52;ATP-adenosine is an important glial signal;409 184.108.40.206;Myelination and importance of the axonal release of ATP;410 220.127.116.11;Astrocyte-mediated, adenosine-dependent heterosynaptic depression;410 18.104.22.168;Behavioral roles for glial-derived ATP and adenosine: respiration and sleep;410 22.214.171.124;pH-dependent release of purines from astrocytes controls breathing;411 126.96.36.199;Microglia and their response to injury;411 188.8.131.52;Adenosine and the effects of alcohol;412 11.8.5;Disorders of the Nervous SystemPurines and Pain: A1R, P2X and P2Y Receptors;412 11.8.6;Disorders of the Nervous System: Adenosine Kinase and the Adenosine Hypothesis of Epilepsy;412 11.8.7;Disorders of the Nervous System: Parkinsons Disease and A2A Antagonists;412 11.8.8;Concluding Comments;413 11.8.9;References;413 11.9;20. Peptides;415 11.9.1;Neuropeptides;415 184.108.40.206;Many neuropeptides were originally identified as pituitary or gastrointestinal hormones;415 220.127.116.11;Peptides can be grouped by structural and functional similarity;416 18.104.22.168;The function of peptides as first messengers is evolutionarily very old;417 22.214.171.124;Vari
ous techniques are used to identify additional neuropeptides;417 126.96.36.199;The neuropeptides exhibit a few key differences from the classical neurotransmitters;417 188.8.131.52;Neuropeptides are often found in neurons with conventional neurotransmitters;418 184.108.40.206;The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters;419 220.127.116.11;Many of the enzymes involved in peptide biogenesis have been identified;419 18.104.22.168;Neuropeptides are packaged into large, dense-core vesicles;424 22.214.171.124;Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modification;424 11.9.2;Neuropeptide Receptors;425 126.96.36.199;Most neuropeptide receptors are seven-transmembrane-domain, G-proteincoupled receptors;425 188.8.131.52;Neuropeptide receptors are not confined to synaptic regions;426 184.108.40.206;Expressions of peptide receptors and the corresponding peptides are not well matched;427 220.127.116.11;The amiloride-sensitive FMRF-amide-gated sodium ion channel is among the few peptide-gated ion channels identified;427 18.104.22.168;Neuropeptide receptors are becoming molecular targets for therapeutic drugs;427 11.9.3;Neuropeptide Functions and Regulation;427 22.214.171.124;The study of peptidergic neurons requires a number of special tools;427 126.96.36.199;Peptides play a role in the plurichemical coding of neuronal signals;428 188.8.131.52;Neuropeptides make a unique contribution to signaling;428 184.108.40.206;Regulation of neuropeptide expression is exerted at several levels;428 11.9.4;Peptidergic Systems in Disease;429 220.127.116.11;Diabetes insipidus occurs with a loss of vasopressin production in the Brattleboro rat model;429 18.104.22.168;Mutations and knockouts of peptide-processing enzyme genes cause a myriad of physiological problems;429 22.214.171.124;Neuropeptides play key roles in appetite regulation and obesity;430 126.96.36.199;Enkephalin knockout mice reach adulthood and are healthy;430 188.8.131.52;Neuropeptides are crucial to
pain perception;431 11.9.5;References;431 12;III. INTRACELLULAR SIGNALING;434 12.1;21. G Proteins;436 12.1.1;Heterotrimeric G Proteins;436 184.108.40.206;The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions;436 220.127.116.11;Multiple forms of heterotrimeric G protein exist in the nervous system;437 18.104.22.168;Each G protein is a heterotrimer composed of single a, ß and . subunits;437 22.214.171.124;The functional activity of G proteins involves their dissociation and reassociation in response to extracellular signals;437 126.96.36.199;G proteins couple some neurotransmitter receptors directly to ion channels;437 188.8.131.52;G proteins regulate intracellular concentrations of second messengers;439 184.108.40.206;G proteins have been implicated in membrane trafficking;440 220.127.116.11;G protein ß. subunits subserve numerous functions in the cell;440 18.104.22.168;The functioning of heterotrimeric G proteins is modulated by other proteins;441 22.214.171.124;G proteins are modified covalently by the addition of long-chain fatty acids;443 126.96.36.199;The functioning of G proteins may be influenced by phosphorylation;443 12.1.2;Small G Proteins;443 188.8.131.52;The best-characterized small G protein is the Ras family, a series of related proteins of 21 kDa;443 184.108.40.206;Rab is a family of small G proteins involved in membrane vesicle trafficking;444 12.1.3;Other Features of G Proteins;444 220.127.116.11;G proteins can be modified by ADP-ribosylation catalyzed by certain bacterial toxins;444 18.104.22.168;G proteins are implicated in the pathophysiology and treatment of disease;445 12.1.4;References;446 12.2;22. Cyclic Nucleotides in the Nervous System;448 12.2.1;Introduction: Second Messengers;448 12.2.2;Adenylyl Cylcases;448 22.214.171.124;Biochemistry of cAMP production;448 126.96.36.199;Adenylyl cyclase isozymes: expression and regulation;450 188.8.131.52.1;Group 1 adenylyl cyclases;450 184.108.40.206.1.1;Adenylyl Cyclase 1;450 220.127.116.11.1.2;Adenylyl Cyclases 3 and 8;451 18.104.22.168.2
;Group 2 adenylyl cyclases;451 22.214.171.124.2.1;Adenylyl Cyclase 2;451 126.96.36.199.2.2;Adenylyl Cyclase 4 and 7;451 188.8.131.52.3;Group 3 adenylyl cyclases;452 184.108.40.206.3.1;Adenylyl Cyclase 5;452 220.127.116.11.3.2;Adenylyl Cyclase 6;452 18.104.22.168.4;Group 4 adenylyl cyclase;452 22.214.171.124.5;Soluble adenylyl cyclase;452 126.96.36.199;Models for cellular regulation of the different types of adenylyl cyclase;452 188.8.131.52;Long-term regulation of adenylyl cyclases;454 184.108.40.206;Molecular targets of cAMP;454 220.127.116.11.1;Protein kinase A;454 18.104.22.168.2;Cyclic nucleotide-gated channels;454 22.214.171.124.3;Epac;455 126.96.36.199.4;Functions of cAMP signaling in the brain;455 188.8.131.52.5;Synaptic plasticity, learning, and memory;455 184.108.40.206.6;Pain;455 220.127.116.11.7;Dopamine signaling in the striatum;455 18.104.22.168.8;Neurodegeneration;455 22.214.171.124.9;Drugs of abuse;455 126.96.36.199.10;Olfaction;455 12.2.3;Guanylyl Cyclases;455 188.8.131.52;Membrane-bound guanylyl cyclase;456 184.108.40.206.1;GC-A, -B and -C are receptors for natriuretic peptides;457 220.127.116.11.2;GC-D and GC-G are implicated in olfaction;457 18.104.22.168.3;GC-E and GC-F are involved in photoreceptor signal transduction;457 22.214.171.124;Soluble guanylyl cyclases;457 126.96.36.199;sGC is regulated by nitric oxide (NO);458 188.8.131.52;Molecular effectors of cGMP signaling;458 184.108.40.206.1;Protein kinase G;458 220.127.116.11.2;cGMP-gated ion channels;458 18.104.22.168.3;Phosphodiesterases;458 22.214.171.124.4;Functions of cGMP signaling in the brain;458 126.96.36.199.5;Synaptic plasticity, learning, and memory;459 188.8.131.52.6;Cognition and mood;459 184.108.40.206.7;Pain;459 12.2.4;Phosphodiesterases;459 220.127.116.11;Structure of phosphodiesterases;459 18.104.22.168;Families of phosphodiesterases;459 22.214.171.124.1;Ca2+/calmodulin-stimulated PDEs (PDE1);459 126.96.36.199.2;cGMP-regulated PDEs (PDE2, PDE3, and PDE11);460 188.8.131.52.3;G proteinactivated phosphodiesterase in retinal phototransduction: PDE6;461 184.108.40.206.4;PDEs regulated primarily by phosphorylation: PDE4, 5 and 10;462 220.127.116.11.5;PDE7, 8 and 9;463 18.104.22.168;Phosphodiesterases a
s pharmacological targets;463 12.2.5;Spatiotemporal Integration and Regulation of Cyclic Nucleotide Signaling in Neurons;463 12.2.6;Conclusion and Future Perspective;464 12.2.7;References;464 12.3;23. Phosphoinositides;467 12.3.1;Introduction;467 12.3.2;The Inositol Lipids;468 22.214.171.124;The three quantitatively major phosphoinositides are structurally and metabolically related;468 126.96.36.199;The quantitatively minor 3'-phosphoinositides are synthesized by phosphatidylinositol 3-kinase;469 188.8.131.52;Phosphoinositides are dephosphorylated by phosphatases;470 184.108.40.206;Phosphoinositides are cleaved by a family of phosphoinositide-specific phospholipase C (PLC) isozymes;471 12.3.3;The Inositol Phosphates;473 220.127.116.11;D-myo-inositol 1,4,5-trisphosphate [i(1,4,5)p3] is a second messenger that liberates Ca2+ from the endoplasmic reticulum via;473 18.104.22.168;The metabolism of inositol phosphates leads to regeneration of free inositol;474 22.214.171.124;Highly phosphorylated forms of myo-inositol are present in cells;474 12.3.4;Diacylglycerol;474 126.96.36.199;Protein kinase C is activated by the second messenger diacylglycerol;474 12.3.5;Phosphoinositides and Cell Regulation;476 188.8.131.52;Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers;476 184.108.40.206.1;Membrane trafficking;476 220.127.116.11.2;Cell growth and cell survival;477 18.104.22.168.3;Regulation of ion channel activity;477 12.3.6;References;478 12.4;24. Calcium;480 12.4.1;The Calcium Signal in Context;480 12.4.2;Calcium Measurement;481 22.214.171.124;Much of our understanding of the essential role of Ca2+ in cellular physiology has been indirect;481 126.96.36.199;Current optical methods to measure calcium use chemical or protein-based fluorescent indicators;481 188.8.131.52.1;The optical monitoring of [Ca2+] relies on indicators whose fluorescence changes upon binding to calcium;481 184.108.40.206.2;Increased resolution can be accomplished optically or by targeting indicator proteins;482 12.4
.3;Calcium Homeostasis at the Plasma Membrane;482 220.127.116.11;The balance between calcium efflux and influx at the plasma membrane determines [Ca2+];482 18.104.22.168;Efflux pathways pumps and transporters;483 22.214.171.124;Influx pathways Ca enters the cell through four major routes;483 12.4.4;Cellular Organelles and Calcium Pools;483 126.96.36.199;The endoplasmic reticulum is the primary intracellular calcium store;484 188.8.131.52;The ER has pumps, storage buffersand Ca2+ release channels;484 184.108.40.206.1;Activation of different ER signaling pathways elicit different responses;484 220.127.116.11.2;Store-operated Ca2+ entry: The ER signals when empty to open channels in the plasma membrane;485 18.104.22.168;Mitochondria have a complex impact on Ca2+ dynamics;485 12.4.5;Ca2+ Signaling Begins in Microdomains;486 12.4.6;Local and Global Ca2+ Signaling: Integrative Roles for Astrocytes?;486 22.214.171.124;Electrically silent astrocytes use Ca2+ as a signaling molecule;486 126.96.36.199;The tripartite synapse: gliotransmitters and modulation of transmission at the synapse;487 188.8.131.52;Astrocyte control of cerebral vasculature;488 12.4.7;Conclusions;489 12.4.8;References;490 12.5;25. Serine and Threonine Phosphorylation;492 12.5.1;Protein Phosphorylation is a Fundamental Mechanism Regulating Cellular Functions;492 184.108.40.206;Phosphorylation levels of substrate proteins are regulated by antagonistic actions of protein kinases and protein phosphatases;493 12.5.2;Protein Ser/Thr Kinases;495 220.127.116.11;Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation;495 18.104.22.168;Second messengerdependent protein Ser/Thr kinases;498 22.214.171.124.1;cAMP-dependent protein kinase;498 126.96.36.199.2;cGMP-dependent protein kinase;498 188.8.131.52.3;Protein kinase C;498 184.108.40.206.4;Calcium2+/calmodulin-dependent kinases;500 220.127.116.11;Second messengerindependent protein Ser/Thr kinases;501 18.104.22.168;The MAPK cascade is a classical example of second messengerindependent protein Ser/Thr kinase signaling;5
01 22.214.171.124.1;Extracellular signal-regulated protein kinases (ERKs);502 126.96.36.199.2;p38 MAPKs;502 188.8.131.52.3;c-Jun NH2-terminal kinases;502 184.108.40.206;The brain contains many other types of second messengerindependent protein Ser/Thr kinases;503 220.127.116.11.1;Cyclin-dependent kinase 5 (CDK5);503 18.104.22.168.2;Glycogen-synthase kinase-3 (GSK3);503 22.214.171.124.3;Casein kinase 1 (CK1);503 126.96.36.199.4;Protein phosphatase 1 (PP1);504 188.8.131.52.5;Protein phosphatase 2A (PP2A);505 184.108.40.206.6;Protein phosphatase 2B (PP2B);505 220.127.116.11.7;Protein phosphatase 2C (PP2C);506 18.104.22.168.8;Dual-specificity phosphatases (DUSPs);506 12.5.3;Protein Ser/Thr Phosphatases;504 22.214.171.124;Common strategies used for the evaluation of neuronal functions of protein kinases and phosphatases;506 12.5.4;Neuronal Phosphoproteins;507 126.96.36.199;Phosphorylation can influence protein function in various ways;507 188.8.131.52.1;Proteins are often subject to complex phosphoregulation;508 184.108.40.206;Cellular signals converge at the level of protein phosphorylation pathways;508 12.5.5;Protein Phosphorylation is a Fundamental Mechanism Underlying Synaptic Plasticity and Memory Functions;509 220.127.116.11;Presynaptic mechanisms regulated by protein phosphorylation;510 18.104.22.168;Postsynaptic mechanisms regulated by protein phosphorylation;512 22.214.171.124;Extrasynaptic mechanisms regulated by protein phosphorylation;514 12.5.6;Protein Phosphorylation in Human Neuronal Disorders;514 126.96.36.199;Genetic neuronal disorders due to mutations in genes of protein kinases and phosphatases;514 188.8.131.52;Protein phosphorylation in pathophysiological processes in diseases of the nervous system;515 184.108.40.206.1;Protein phosphorylation and AD;515 12.5.7;Acknowledgments;516 12.5.8;References;516 12.6;26. Tyrosine Phosphorylation;518 12.6.1;Tyrosine Phosphorylation in the Nervous System;518 12.6.2;Protein Tyrosine Kinases;519 220.127.116.11;Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper;519
18.104.22.168;Receptor protein tyrosine kinases consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domain;523 22.214.171.124.1;RPTK Activation;525 126.96.36.199.2;RPTK Inactivation;525 188.8.131.52.3;Tyrosine Phosphorylation of RPTKs;526 12.6.3;Protein Tyrosine Phosphatases;526 184.108.40.206;Protein tyrosine phosphatases are structurally different from serinethreonine phosphatases and contain a cysteine residue;528 220.127.116.11;Nonreceptor tyrosine phosphatases are cytoplasmic and have regulatory sequences flanking the catalytic domain;529 18.104.22.168;Receptor protein tyrosine phosphatases consist of an extracellular domain, a transmembrane domain and one or two intracellular;530 22.214.171.124;Dual-specificity phosphatases are a diverse family defined by the signature cysteine-containing motif of PTPs;530 12.6.4;Role of Tyrosine Phosphorylation in the Nervous System;530 126.96.36.199;Tyrosine phosphorylation is involved in every stage of neuronal development;530 188.8.131.52;Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse;534 184.108.40.206;Tyrosine phosphorylation contributes to the formation of synapses in the central nervous system;534 220.127.116.11.1;Acetylcholine Receptors;535 18.104.22.168.2;N-Methyl-d-Aspartate Receptors;535 22.214.171.124.3;GABA Receptors;536 126.96.36.199.4;Voltage-Gated Ion Channels;536 12.6.5;References;536 12.7;27. Transcription Factors in the Central Nervous System;539 12.7.1;The Transcriptional Process;539 188.8.131.52;Co-regulators of transcriptionmodulation of chromatin structure;541 184.108.40.206;Histone acetylation;541 220.127.116.11;Histone and DNA methylation;542 12.7.2;Regulation of Transcription by Transcription Factors;543 18.104.22.168;Technology that has hastened the study of transcription;543 22.214.171.124;NextGen sequencing to assess the cellular transcriptome;545 12.7.3;Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors;546 126.96.36.199;Corticosteroid receptors regulate transcription in the nervous system;547 188.8.131.52;The mechanisms of
corticosteroid receptor regulation of transcription have been elucidated;547 12.7.4;camp Regulation of Transcription;549 184.108.40.206;The cAMP response elementbinding protein is a member of a family containing interacting proteins;550 220.127.116.11;The function of the cAMP response elementbinding protein has been modeled in transgenic organisms;550 12.7.5;The Role of Transcription Factors in Cellular Phenotype;552 18.104.22.168;Transcription factors navigate the roadmap of cellular maturation;552 22.214.171.124;Ectopic expression of transcription factors can reprogram differentiated cells to induce stemness;552 12.7.6;The Transcriptome Dictates Cellular Phenotype;553 12.7.7;Transcription as a Target for Drug Development;553 12.7.8;References;554 13;IV. GROWTH, DEVELOPMENT AND DIFFERENTIATION;556 13.1;28. Development of the Nervous System;558 13.1.1;Introduction;558 13.1.2;Early Embryology of the Nervous System;559 126.96.36.199;The CNS arises from the neural tube;559 188.8.131.52;The major divisions of the CNS are identifiable early in development;559 13.1.3;Spatial Regionalization;559 184.108.40.206;A dorsoventral pattern arises with signals from adjacent non-neuronal cells;559 220.127.116.11;The rostrocaudal axis is specified by homeobox-containing genes;560 18.104.22.168;Embryonic signaling centers organize large regions of the brain;563 13.1.4;Neurogenesis and Gliogenesis;564 22.214.171.124;Neurons have a birthdate;564 126.96.36.199;Reelin and notch signaling contribute to cortical layer organization;564 188.8.131.52;Neuronal specification involves proneural and neurogenic gene gunctions;565 13.1.5;PNS Development and Target Interactions;566 184.108.40.206;The neural crest gives rise to PNS derivatives by induction;566 13.1.6;Axon Guidance Contributes to Correct Connections;567 220.127.116.11;Naturally occurring cell death eliminates cells and synapses;567 13.1.7;Synapse Formation;568 18.104.22.168;The neuromuscular junction between motor neurons and muscle cells;568 13.1.8;Activity and Experience Shape Long-Lasting Connections;568 13.1.
9;Summary;569 13.1.10;References;570 13.2;29. Growth Factors;571 13.2.1;Introduction: What is a Growth Factor?;571 13.2.2;Neurotrophins;572 22.214.171.124;Nerve growth factor;572 126.96.36.199;Brain-derived neurotrophic factor;573 188.8.131.52;Neurotrophin 3;575 184.108.40.206;Neurotrophin 4;575 13.2.3;Regulation of Neurotrophin Expression;576 13.2.4;Proneurotrophins;576 13.2.5;Neurotrophin Receptors;576 220.127.116.11;Trk receptors;577 18.104.22.168;The p75 neurotrophin receptor (p75NTR);577 13.2.6;Glial Cell lineDerived Neurotrophic Factor (GDNF);578 13.2.7;GFL Receptors;579 13.2.8;Neuregulins;580 13.2.9;Neurotrophic Cytokines;580 13.2.10;Summary and Conclusions;582 13.2.11;References;582 13.3;30. Stem Cells in the Nervous System;583 13.3.1;Introduction/Overview;583 13.3.2;Stem Cells are Multipotent and Self-Renewing;583 22.214.171.124;Embryonic stem (ES) cells are derived from the inner cell mass of embryos;584 126.96.36.199;Hematopoietic stem cells (HSC) in bone marrow reconstitute the blood;584 13.3.3;Neural Stem Cells Contribute to Neurons and Glia During Normal Development;584 188.8.131.52;Neural stem cells (NSCs);585 184.108.40.206;Radial glia are stem cells;585 220.127.116.11;The peripheral nervous system (PNS) is derived from neural crest stem cells;585 13.3.4;Stem Cells can be Identified Antigenically and Functionally;586 18.104.22.168;Stem cell markers in the nervous system;586 22.214.171.124;The neurosphere functional assay;586 126.96.36.199;Is there a brain neoplasm stem cell?;587 188.8.131.52;Induced pluripotent stem cells, reprogramming and directed differentiation;587 13.3.5;Stem Cells Offer Potential for Repair in the Adult Nervous System;588 184.108.40.206;Stem cells to replace depleted neurochemicals: Parkinsons disease;588 220.127.116.11;Stem cell treatment to deliver missing enzymes or proteins: leukodystrophies;589 18.104.22.168;Stem cells for cell replacement therapy: myelin;589 22.214.171.124;Stem cells as a source of growth factors and guidance cues;590 126.96.36.199;Stem cells for immunomodulation: multiple sclerosis;591 188.8.131.52;Common challen
ges for stem cell therapy in the nervous system;591 13.3.6;References;592 13.4;31. Formation and Maintenance of Myelin;594 13.4.1;Introduction;594 184.108.40.206;Myelination occurs during nervous system development and is essential for normal nervous system function;595 13.4.2;Schwann Cell Development;595 220.127.116.11;Schwann cells are the myelinating cells of the peripheral nervous system;595 18.104.22.168;Schwann cell lineage differentiation is regulated by a series of transcription factors;595 13.4.3;Oligodendrocyte Development;595 22.214.171.124;Oligodendrocytes are the myelinating cells of the CNS;595 126.96.36.199;Much early work was possible because of in vitro analysis of the oligodendrocyte cell lineage;595 188.8.131.52;The discovery of several transcription factors that are expressed at early stages of oligodendrocyte specification and;596 184.108.40.206;A number of transcriptional and epigenetic regulators control oligodendrocyte progenitor cell differentiation into;597 13.4.4;Regulation of Myelination;599 220.127.116.11;Extensive recent research has focused on identifying the axonal signals that regulate myelination;599 13.4.5;Developmental and Metabolic Aspects of Myelin;600 18.104.22.168;Synthesis of myelin components is very rapid during deposition of myelin;600 22.214.171.124;Sorting and transport of lipids and proteins takes place during myelin assembly;600 126.96.36.199;The composition of myelin changes during development;601 13.4.6;Genetic Disorders of Myelination;601 188.8.131.52;Rodent mutants of myelination have been investigated since the 1950s;601 13.4.7;Myelin Maintenance;602 184.108.40.206;Maintenance of myelin once it is formed is a poorly understood process;602 220.127.116.11;Myelin components exhibit great heterogeneity of metabolic turnover;602 18.104.22.168;There are signal transduction systems in myelin sheaths;602 22.214.171.124;The dynamic nature of myelin sheaths likely contributes to the functional state of axons;603 126.96.36.199;Peripheral neuropathies result from loss of myelin in the peripheral nervous system;603 1
188.8.131.52;A number of environmental toxins impact myelination during development or myelin maintenance in the adult;603 184.108.40.206;Leukodystrophies define a number of genetic disorders that impact CNS myelination (dysmyelination) or myelin maintenance once;603 13.4.8;Remyelination;604 220.127.116.11;Peripheral nerve regeneration has been studied extensively;604 18.104.22.168;Demyelination in the CNS has far more extensive long-term consequences than in the PNS, since a single oligodendrocyte can;605 13.4.9;Acknowledgments;605 13.4.10;References;605 13.5;32. Axonal Growth in the Adult Mammalian Nervous System: Regeneration and Compensatory Plasticity;607 13.5.1;Introduction;607 13.5.2;Regeneration in the Peripheral Nervous System;608 22.214.171.124;Wallerian degeneration is the secondary disruption of the myelin sheath and axon distal to the injury;608 126.96.36.199;The molecular and cellular events during Wallerian degeneration in the PNS transform the damaged nerve into an environment;608 188.8.131.52;Both Schwann cells and basal lamina are required for axonal regeneration to proceed;609 184.108.40.206;Cell surface adhesion molecules, which promote regeneration, are expressed on plasmalemma of both Schwann cells and regenerating;610 220.127.116.11;Structural and biochemical changes occur after axotomy;610 13.5.3;Regeneration in the Central Nervous System;610 18.104.22.168;Central nervous system myelin contains molecules that inhibit neurite growth;610 22.214.171.124;Nogo-A is a potent inhibitor of neurite growth and blocks axonal regeneration in the central nervous system;611 126.96.36.199;Nogo gene is a member of the reticulon superfamily;612 188.8.131.52;Nogo-A function-blocking antibodies and peptides lead to axonal growth and functional recovery in vivo;613 184.108.40.206;Lines of knockout mice null for the Nogo genes have been developed;613 220.127.116.11;Additional myelin components have growth-inhibitory activity;613 18.104.22.168;Inhibition of neurite growth is mediated through surface receptors and intracellular signaling molecules;6
14 22.214.171.124;Neuronal expression of Nogo-A regulates neurite outgrowth;614 126.96.36.199;Axon growth is inhibited by the glial scar;614 188.8.131.52;Neurotrophic factors promote both cell survival and axon growth after adult CNS injury in vivo;615 13.5.4;Central Nervous System Injury and Compensatory Plasticity;615 184.108.40.206;Neonatal brain damage results in compensatory plasticity;615 220.127.116.11;Compensatory plasticity and functional recovery can be enhanced in the injured adult central nervous system through blockade;616 13.5.5;Summary;617 13.5.6;Acknowledgments;618 13.5.7;References;618 14;V. CELL INJURY AND INFLAMMATION;620 14.1;33. Molecular Mechanisms and Consequences of Immune and Nervous System Interactions;622 14.1.1;Introduction;622 18.104.22.168;Definition: What is neuroimmunology?;622 22.214.171.124;Scope: Are neuroimmune interactions relevant only in the context of immune-mediated neurodegenerative disorders?;623 126.96.36.199;Relevance: A real-world example;623 14.1.2;Distinguishing Friend from FOE;624 188.8.131.52;Innate versus adaptive immunity: two interacting types of immune recognition;624 184.108.40.206.1;Innate immunity is triggered by evolutionarily conserved alarm signals;624 220.127.116.11.2;Adaptive immunity can recognize evolutionarily novel molecules;624 18.104.22.168.3;Antigen presentation by major histocompatibility-complexexpressing cells is required to activate T-cells;624 22.214.171.124.4;Antigen-activated T-cells regulate the activation of innate immune cells;626 126.96.36.199.5;The activation state of the antigen-presenting cell regulates T cell activation and phenotype;626 188.8.131.52;Choosing between immune tolerance and inflammation;626 184.108.40.206.1;Antigen presentation in the absence of alarm signals promotes tolerance;627 220.127.116.11.2;PAMP and DAMP signals shape APC function and T-cell differentiation;627 14.1.3;The Nervous System Regulates Both Innate and Adaptive Immunity;627 18.104.22.168;Functional consequences of lymphoid tissue innervation;627 22.214.171.124;Neuropeptides are potent modulators of an
tigen-presenting cell function;628 14.1.4;Immune Privilege Is Not Immune Isolation: The CNS as an Immune-Active Organ;628 126.96.36.199;The BBB and CNS-specific regulation of leukocyte influx and efflux;629 188.8.131.52;Leukocyte migration into the CNS parenchyma is a two-step process;629 184.108.40.206;Microglia, a CNS-specific macrophage and antigen-presenting cell;630 220.127.116.11.1;Distinguishing CNS-resident microglia from CNS-infiltrating macrophages;630 18.104.22.168.2;Microglia are not effective at initiating antigen-driven T-cell functions;631 22.214.171.124;The CNS microenvironment actively regulates the phenotype of microglia and infiltrating immune cells;631 14.1.5;Immune-Regulated Changes in Neuronal Function and Mammalian Behavior;632 14.1.6;Summary: Manipulating Neuroimmune Interactions;633 14.1.7;References;633 14.2;34. Neuroinflammation;635 14.2.1;Neuroinflammation: Introduction;635 126.96.36.199;The role of microglia in neuroinflammation;636 14.2.2;The Highly Regulated Activation of Microglia and Phagocytosis;637 188.8.131.52;Microglial activation;637 184.108.40.206;Microglial phagocytosis;637 220.127.116.11;Receptors in microglia;637 18.104.22.168;Microglia in neurodegenerative diseases;638 14.2.3;Microglial Dysfunction During Aging;638 14.2.4;Protein Aggregation;638 22.214.171.124;The effects of protein aggregation on microglial function;639 14.2.5;Cytokines/Chemokines;639 126.96.36.199;Cytokines are responsible for microglia activation;639 188.8.131.52;Cytokines are produced by activated microglia;639 184.108.40.206;Anti-inflammatory interleukin-10 and TGF-ß1;639 14.2.6;Lipid Mediator Pathways in Neuroinflammation;639 220.127.116.11;Initiation of inflammation: prostaglandin and leukotriene pathways;639 18.104.22.168;Resolution of inflammation: lipoxin, resolvin, and neuroprotectin pathways;641 14.2.7;Ischemia-Reperfusion Damage;641 14.2.8;The Interface Between Inflammation and the Immune System in the CNS;641 22.214.171.124;Aß Immunotherapy;641 126.96.36.199;The inflammasome;641 14.2.9;Mitochondria: A Connection Between Inflammation and Neuro
degeneration;642 14.2.10;Neuroprotective Signaling Circuits;642 14.2.11;References;643 14.3;35. Brain Ischemia and Reperfusion: Cellular and Molecular Mechanisms in Stroke Injury;646 14.3.1;Brain Responses to Ischemia;646 188.8.131.52;Focal cerebral ischemia;647 184.108.40.206;Global cerebral ischemia;648 14.3.2;Injury in the Ischemic Phase;652 220.127.116.11;Excitotoxic glutamate neurotransmitter;652 18.104.22.168;Excitotoxicity;652 22.214.171.124;Ca2+ overloading in the ischemic injury;652 126.96.36.199;NMDA receptors, brain function and cell death;653 188.8.131.52;Downstream cell death signals of NMDA receptors;654 14.3.3;Brain Injury During the Reperfusion Phase: Free Radicals in IschemiaReperfusion Injury;654 184.108.40.206;Reactive oxygen species contribute to the injury;654 220.127.116.11;Mitochondria, nitric oxide synthase and polyunsaturated fatty acid metabolism are sources of reactive oxygen species during;655 18.104.22.168;Polyunsaturated fatty acids generate reactive oxygen species;655 22.214.171.124;Brain antioxidants contribute to the protection of brain from ischemiareperfusion injury;655 126.96.36.199;Reactive oxygen species enhance the excitotoxic and the apoptotic consequences of ischemic brain damage;656 14.3.4;Breakdown of the Neurovascular Unit and Brain Edema;656 188.8.131.52;Metalloproteinases during the neurovascular unit disruption;656 184.108.40.206;Significance of aquaporins in brain edema;657 14.3.5;Neuroprotection Signaling and Resolution of Inflammation: Mechanisms;657 220.127.116.11;Inflammatory mediators and anti-inflammatory regulation;657 18.104.22.168;Apoptotic signaling;658 22.214.171.124;Docosanoids and penumbra protection;660 14.3.6;Potential Therapeutic Strategies for Acute Ischemic Stroke;663 14.3.7;Acknowledgments;665 14.3.8;References;665 14.4;36. Lipid Mediators: Eicosanoids, Docosanoids and Platelet-Activating Factor;668 14.4.1;Storage of Lipid Messengers in Neural Membrane Phospholipids;669 126.96.36.199;Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli
;669 188.8.131.52;Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli;670 184.108.40.206;Phospholipids in synaptic membranes are an important target in seizures, traumatic brain injury, neurodegenerative diseases;670 220.127.116.11;Some molecular species of phospholipids in excitable membranes are reservoirs of bioactive lipid mediators that act as;670 18.104.22.168;Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second;670 14.4.2;Phospholipases A2;672 22.214.171.124;Phospholipases A2 catalyze the cleavage of the fatty acyl chain from the sn-2 carbon of the glycerol backbone of phospholipids;672 126.96.36.199;Cytosolic phospholipases A2 are involved in bioactive lipid formation;672 188.8.131.52;Ischemia and seizures activate phospholipases A2, releasing arachidonic and docosahexaenoic acids;672 184.108.40.206;Secretory phospholipases A2 are of relatively low molecular weight and have a high number of disulfide bridges, making them;672 220.127.116.11;There are high-affinity receptors that bind secretory phospholipases A2;672 14.4.3;Eicosanoids;673 18.104.22.168;Arachidonic acid is converted to biologically active derivatives by cyclooxygenases and lipoxygenases;673 22.214.171.124;Prostaglandins are very rapidly released from neurons and glial cells;673 126.96.36.199;Arachidonic acid is also the substrate for lipoxygenases and, as in the case of cyclooxygenases, molecular oxygen is required;674 14.4.4;Platelet-Activating Factor;674 188.8.131.52;Platelet-activating factor is a very potent and short-lived lipid messenger;675 184.108.40.206;Ischemia and seizures increase platelet-activating factor content in the brain;677 14.4.5;Cyclooxygenases;677 220.127.116.11;The cyclooxygenases are heme-containing enzymes that convert arachidonic acid to prostaglandin H2;677 18.104.22.168;Platelet-activating factor is a transcriptional activator of cyclooxygenase-2;677 22.214.171.124;COX-derived AA metabolites play multiple important roles i
n CNS;677 126.96.36.199;Cyclooxygenase-2 participates in aberrant synaptic plasticity during epileptogenesis;677 14.4.6;Lipoxygenases;678 188.8.131.52;The lipoxygenases are involved in the rate-determining step in the biosynthesis of leukotrienes, lipoxins, resolvins, and protectins;678 184.108.40.206;5-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 5-position to form 5-HpETE;678 220.127.116.11;15-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 15-position to Form 15-HpETE;678 18.104.22.168;LOs and LO-derived products play important roles in a variety of inflammatory disorders;679 14.4.7;Diacylglycerol Kinases;679 22.214.171.124;The slow glutamate responses are mediated through metabotropic receptors coupled to G proteins;679 14.4.8;Lipid Signaling in Neuroinflammation;679 126.96.36.199;A platelet-activating-factor-stimulated signal-transduction pathway is a major component of the kainic-acid-induced;679 188.8.131.52;In cerebrovascular diseases, the phospholipase-A2-related signaling triggered by ischemiareperfusion may be part of a delicate;679 184.108.40.206;Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, are products of membrane lipid breakdown;679 220.127.116.11;Free fatty acid release during cerebral ischemia is a complex process that includes the activation of signaling cascades;680 18.104.22.168;The rate of free fatty acid production in the mammalian brain correlates with the extent of resistance to ischemia;681 22.214.171.124;Activation of the arachidonic acid cascade during ischemiareperfusion is a multistage process;681 126.96.36.199;Cyclooxygenase and lipoxygenase products accumulate during reperfusion following cerebral ischemia;681 188.8.131.52;The cerebrovasculature is also an abundant source of eicosanoids;681 14.4.9;Docosahexaenoic Acid;681 184.108.40.206;Brain and retina are the tissues containing the highest contents of docosahexaenoic acid;681 220.127.116.11;Rhodopsin in photoreceptors is immersed in a lipid environment highly enriched in phospholipids containin
g docosahexaenoic;681 14.4.10;Lipid Peroxidation and Oxidative Stress;682 18.104.22.168;Docosahexaenoic-acidcontaining phospholipids are targets for lipid peroxidation;682 14.4.11;Docosanoids;682 22.214.171.124;Sequential oxygenation of DHA leads to several types of potent bioactive lipid mediators, including resolvins and protectins;682 14.4.12;Neuroprotectin D1: A Docosahexaenoic-AcidDerived Mediator;682 126.96.36.199;Docosanoids, enzyme-derived docosahexaenoic acid metabolites, were identified initially in the retina;682 188.8.131.52;Neuroprotectin D1 is a potent inhibitor of brain ischemiareperfusion-induced PMN infiltration, as well as of NF-.B and COX-2 expression;682 14.4.13;The Future of Neurolipidomic Signaling;682 184.108.40.206;Knowledge of the significance of lipid signaling in the nervous system is being expanded by advances in experimental approaches;682 220.127.116.11;Understanding of the fundamental workings of the dendrites, which contain complex intracellular membranes rich in polyunsaturated;683 18.104.22.168;Arachidonic acid is widely implicated in signaling in brain, and research continues toward understanding the release of this fatty;683 22.214.171.124;The knowledge evolving from lipidomic neurobiology will be potentiated by multidisciplinary approaches such as multiphoton;685 14.4.14;References;685 14.5;37. Apoptosis and Necrosis;688 14.5.1;Distinguishing Features of Apoptosis and Necrosis;688 126.96.36.199;During embryonic and postnatal development, and throughout adult life, many cells in the nervous system die;688 188.8.131.52;Many of the morphological and biochemical changes that occur in cells that die by necrosis are very different from those that occur in apoptosis;689 14.5.2;Apoptosis;689 184.108.40.206;Adaptive apoptosis occurs in the developing and adult nervous system;689 220.127.116.11;Apoptosis occurs in acute neurological insults;690 18.104.22.168;Apoptosis occurs in neurodegenerative disorders;692 22.214.171.124;There are many triggers of apoptosis;693 126.96.36.199.1;Insufficient trophic support;6
93 188.8.131.52.2;Death receptor activation;693 184.108.40.206.3;DNA damage;693 220.127.116.11.4;Oxidative and metabolic stress;693 18.104.22.168;Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process;694 22.214.171.124;Several different changes in mitochondria occur during apoptosis;695 126.96.36.199;The postmitochondrial events of apoptosis include activation of the caspases;695 188.8.131.52;A widely used criterion for identifying a cell as apoptotic is nuclear chromatin condensation and fragmentation;695 184.108.40.206;Cells in the nervous system possess different mechanisms to prevent apoptosis;695 220.127.116.11.1;Neurotrophic factors, cytokines and cell adhesion molecules;695 18.104.22.168.2;Antiapoptotic proteins;696 22.214.171.124.3;Hormesis-based mechanisms;696 126.96.36.199.4;Antioxidants and calcium-stabilizing proteins;696 188.8.131.52;The morphological and biochemical characteristics of apoptosis are not always manifest in cells undergoing programmed cell ...;697 184.108.40.206;Apoptotic cascades can be triggered, and pre- and postmitochondrial events can occur, without the cell dying;697 14.5.3;Necrosis;697 220.127.116.11;Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates;697 18.104.22.168;There are few cell death triggers that are only capable of inducing either apoptosis or necrosis;697 22.214.171.124.1;Trauma;697 126.96.36.199.2;Energy failure/ischemia;697 188.8.131.52.3;Excitotoxicity;698 14.5.4; TARGETING Apoptosis and Necrosis in Neurological DISORDERS;698 14.5.5;References;700 15;VI. INHERITED AND NEURODEGENERATIVE DISEASES;702 15.1;38. Peripheral Neuropathy: Neurochemical and Molecular Mechanisms;704 15.1.1;Introduction;704 15.1.2;Peripheral Nerve Organization;705 184.108.40.206;The peripheral nervous system (PNS) includes the cranial nerves, the spinal nerves and nerve roots, the peripheral nerves;705 15.1.3;Genetically Determined Neuropathies;705 220.127.116.11;The inherited neuropathies are commonly referred to a
s Charcot-Marie-Tooth disorders (CMT) or hereditary motor and sensory;705 15.1.4;Diabetic Neuropathy;709 18.104.22.168;Metabolic/Endocrine diseases such as diabetes mellitus (DM), thyroid diseases, and uremia are frequent causes of peripheral nerve damage;709 15.1.5;Autoimmune Neuropathies;709 22.214.171.124;An autoimmune attack on the PNS can manifest in various disease forms that include but are not limited to Guillain-Barré;709 15.1.6;Other Causes of Peripheral Nerve Disorders;712 126.96.36.199;Infections can damage nerves directly, via exotoxins, or by immune mechanisms;712 188.8.131.52;Peripheral nerve damage is a recognized complication of toxins (e.g., alchohol, heavy metals, hexacarbons, organophosphates;712 184.108.40.206;Nutritional and vitamin deficiencies that occur during famine, after gastric surgery for tumors, or, more recently, following;712 15.1.7;Axon Degeneration and Protection;712 15.1.8;References;713 15.2;39. Diseases Involving Myelin;716 15.2.1;General Classification;717 220.127.116.11;Myelin deficiency can result from failure of synthesis during development or from myelin breakdown after its formation;717 18.104.22.168;Many of the biochemical changes associated with CNS demyelination are similar regardless of etiology;717 15.2.2;Acquired Immune-Mediated and/or Infectious Diseases of Myelin;717 22.214.171.124;Nervous system damage in acquired demyelinating diseases is selectively against myelin or myelin-forming cells, but axons;717 126.96.36.199;Multiple sclerosis (MS) is the most common demyelinating disease of the CNS in humans;717 188.8.131.52.1;Diagnosis;717 184.108.40.206.2;Pathology;718 220.127.116.11.3;Gray matter lesions;718 18.104.22.168.4;Axonal and neuronal pathology;719 22.214.171.124.5;Biochemistry;719 126.96.36.199.6;Therapy;720 188.8.131.52.7;Etiology;720 184.108.40.206.8;Epidemiology and natural history of MS;720 220.127.116.11.9;Environmental factors;720 18.104.22.168.10;Genetics;721 22.214.171.124.11;Immunology;721 126.96.36.199.12;Perspectives for future research;721 188.8.131.52;Animal models are required to understand the pathogenesis
of MS and test the efficacy of possible therapeutic interventions;721 184.108.40.206.1;Viral models;721 220.127.116.11.2;Experimental allergic encephalomyelitis;722 18.104.22.168.3;Toxins;722 22.214.171.124;Other acquired disorders affecting CNS myelin have an immune-mediated or infectious pathogenesis;722 126.96.36.199.1;Acute disseminated encephalomyelitis;722 188.8.131.52.2;Progressive multifocal leukoencephalopathy;722 184.108.40.206;Some human peripheral neuropathies involving demyelination are immune mediated;722 220.127.116.11.1;Paraproteinemic polyneuropathy;723 18.104.22.168.2;GuillainBarré syndrome;723 22.214.171.124.3;Chronic inflammatory demyelinating polyneuropathy;724 15.2.3;Genetically Determined Disorders of Myelin;724 126.96.36.199;The human leukodystrophies are inherited disorders of CNS white matter;724 188.8.131.52.1;Lysosomal storage diseases;724 184.108.40.206.2;Other leukodystrophies;726 220.127.116.11;Deficiencies of peripheral nerve myelin in common inherited human neuropathies are caused by mutations in a variety of genes;726 15.2.4;Other Diseases Primarily Involving Myelin;726 18.104.22.168;Myelin formation and stability are affected by a variety of other etiologies including developmental insults, nutritional;726 15.2.5;Disorders Primarily Affecting Neurons with Secondary Involvement of Myelin;727 22.214.171.124;Many insults to the nervous system initially cause damage to neurons but eventually result in regions of demyelination as;727 15.2.6;Repair in Demyelinating Diseases;727 126.96.36.199;The capacity for remyelination depends upon the presence of receptive axons and sufficient myelin-forming cells;727 188.8.131.52;Spontaneous remyelination of lesions of MS is well documented, but remyelination is usually incomplete;728 184.108.40.206;Remyelination in the CNS can be promoted by various treatments;728 15.2.7;Acknowledgments;728 15.2.8;References;728 15.3;40. The Epilepsies: Phenotypes and Mechanisms;730 15.3.1;Epilepsy is a Common Neurological Disorder;730 15.3.2;Terminology and Classification;730 220.127.116.11;Disrupting the delicate bala
nce of inhibitory and excitatory synaptic transmission can trigger the disordered, synchronous;731 18.104.22.168;Cellular mechanisms underlying hyperexcitability have been analyzed by electrophysiological studies of hippocampal slices;733 22.214.171.124;Normally the dentate granule cells of hippocampus limit excessive activation of their targets, the CA3 pyramidal cells;733 126.96.36.199;Analyses of afferents of dentate granule cells from epileptic animals reveal abnormal inhibitory and excitatory synaptic input;734 188.8.131.52;Axonal and dendritic sprouting lead to abnormal recurrent excitatory synaptic circuits among the dentate granule cells in epileptic brain;734 184.108.40.206;Epileptogenesis is the process by which a normal brain becomes epileptic;734 220.127.116.11;Identifying molecular mechanisms of epileptogenesis will provide new targets for developing small molecules to prevent epilepsy;735 15.3.3;Mechanisms of Antiseizure Drugs;736 18.104.22.168;Many antiseizure drugs act on voltage-gated sodium channels to limit high-frequency, but not low-frequency, firing of neurons;736 22.214.171.124;Other antiseizure drugs enhance GABA-mediated synaptic inhibition;736 126.96.36.199;Other antiseizure drugs regulate a subset of voltage-gated calcium currents;737 15.3.4;Genetics of Epilepsy;738 188.8.131.52;Many forms of epilepsy have genetic determinants;738 184.108.40.206;Some spontaneous and some engineered mutations of mice result in epilepsy;740 15.3.5;References;742 15.4;41. Genetics of Neurodegenerative Diseases;744 15.4.1;Genetic Aspects of Common Neurodegenerative Diseases;744 15.4.2;Alzheimers Disease;746 220.127.116.11;Early onset familial AD;746 18.104.22.168;Apolipoprotein E in late-onset AD;746 22.214.171.124;Genome-wide screening in late-onset AD;747 15.4.3;Parkinsons Disease;748 126.96.36.199;Autosomal-dominant forms of PD;748 188.8.131.52;Autosomal-recessive forms of PD;748 184.108.40.206;Candidate-gene studies and genome-wide screening in PD;749 15.4.4;Dementia with Lewy Bodies;750 220.127.116.11;The genetics of DLB shows similarities with both
PD and AD;750 15.4.5;Frontotemporal Dementia;751 18.104.22.168;Genetic determinants of tau-positive FTLD;751 22.214.171.124;Genetic determinants of tau-negative FTLD;751 15.4.6;Amyotrophic Lateral Sclerosis;752 126.96.36.199;Familial ALS;752 15.4.7;Neurodegenerative Triplet Repeat Disorders;754 188.8.131.52;Huntingtons disease (HD);754 15.4.8;Creutzfeld-JaKob Disease and other Prion Diseases;755 184.108.40.206;PRNP mutations are causal and influence disease progression;755 15.4.9;Concluding Remarks;756 15.4.10;References;758 15.5;42. Disorders of Amino Acid Metabolism;762 15.5.1;Introduction;763 220.127.116.11;An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid;763 18.104.22.168;The major metabolic fate of amino acids is conversion into organic acids; absent an enzyme to oxidize an organic acid, an organic aciduria results;763 22.214.171.124;Untreated aminoacidurias can cause brain damage in many ways, often through impairing brain energy metabolism;763 126.96.36.199;An imbalance of amino acids in the blood often alters the rate of transport of these compounds into the brain, thereby affecting levels of neurotransmitters;765 188.8.131.52;Treatment of aminoacidurias with a low-protein diet may influence brain chemistry;767 184.108.40.206;Imbalances of brain amino acids may hinder the synthesis of brain lipids, leading to a diminution in the rate of myelin formation;767 220.127.116.11;In many aminoacidurias, there may occur deficits in neurotransmitters and receptors, particularly the N-methyl-d-aspartate receptor;767 18.104.22.168;Brain edema, often associated with increased intracranial pressure, may accompany the acute phase of metabolic decompensation in the aminoacidurias;767 15.5.2;Disorders of Branched-Chain Amino Acids: Maple Syrup Urine Disease;767 22.214.171.124;Maple syrup urine disease involves a congenital failure to oxidize the three branched-chain amino acids;767 126.96.36.199;Effective treatment of maple syrup urine disease involves the restriction of dietary branched-c
hain amino acids;768 15.5.3;Disorders of Phenylalanine Metabolism: Phenylketonuria;768 188.8.131.52;Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase;768 184.108.40.206;The outlook for patients who are treated at an early age is favorable;769 220.127.116.11;Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway;769 15.5.4;Disorders of Glycine Metabolism: Nonketotic Hyperglycinemia;769 18.104.22.168;Nonketotic hyperglycinemia results from the congenital absence of the glycine cleavage system, which mediates the interconversion of glycine and serine;769 22.214.171.124;Nonketotic hyperglycinemia causes a severe seizure disorder and profound brain damage;769 126.96.36.199;Treatment for nonketotic hyperglycinemia is less effective than that available for other aminoacidurias;770 15.5.5;Disorders of Sulfur Amino Acid Metabolism: Homocystinuria;770 188.8.131.52;The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids;770 184.108.40.206;Homocystinuria is the result of the congenital absence of cystathionine synthase, a key enzyme of the transsulfuration pathway;772 220.127.116.11;Homocystinuria can be treated in some cases by the administration of pyridoxine (Vitamin B6), which is a cofactor for the cystathionine synthase reaction;772 18.104.22.168;Patients with homocystinuria are at risk for cerebrovascular and cardiovascular disease and thromboses;772 22.214.171.124;Prognosis is more favorable in the pyridoxine-responsive patients;772 126.96.36.199;Homocystinuria can occur when homocysteine is not remethylated back to form methionine;773 188.8.131.52;One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine;773 184.108.40.206;Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria;773 220.127.116.11;Cobalamin-c disease: remethylation of homocysteine to meth
ionine also requires an activated form of vitamin B12;773 18.104.22.168;Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration;774 15.5.6;The Urea Cycle Defects;774 22.214.171.124;The urea cycle is essential for the detoxification of ammonia;774 126.96.36.199;Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant;775 188.8.131.52.1;Carbamyl phosphate synthetase deficiency;775 184.108.40.206.2;N-Acetylglutamate synthetase deficiency;775 220.127.116.11.3;Ornithine transcarbamylase deficiency;775 18.104.22.168.4;Citrullinemia;775 22.214.171.124.5;Argininosuccinic aciduria;776 126.96.36.199.6;Arginase deficiency;776 188.8.131.52;Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle;776 184.108.40.206.1;Hyperornithinemia, hyperammonemia, homocitrullinuria;776 220.127.116.11.2;Lysinuric protein intolerance;776 18.104.22.168;Successful management of urea cycle defects involves a low-protein diet to minimize ammonia production as well as medication;776 15.5.7;Disorders of Glutathione Metabolism;777 22.214.171.124;The tripeptide glutathione is the major intracellular antioxidant;777 126.96.36.199.1;5-Oxoprolinuria: glutathione synthetase deficiency;777 188.8.131.52.2;.-Glutamylcysteine synthetase deficiency;777 184.108.40.206.3;.-Glutamyltranspeptidase deficiency;777 220.127.116.11.4;5-Oxoprolinase deficiency;777 15.5.8;Disorders of g-Aminobutyric Acid Metabolism;777 18.104.22.168;Congenital defects in the metabolism of .-aminobutyric acid have been described;777 22.214.171.124.1;Pyridoxine dependency;778 126.96.36.199.2;.-Aminobutyric acid transaminase deficiency;778 188.8.131.52.3;Succinic semialdehyde dehydrogenase deficiency;778 15.5.9;Disorders of N-Acetyl Aspartate Metabolism;778 184.108.40.206;Canavans disease is the result of a deficiency of the enzyme that breaks down N-acetylaspartate, an important donor of acetyl groups for brain;778 15.5.10;References;778 15.6;43. Inborn Metabolic Defects of Lyso
somes, Peroxisomes, Carbohydrates, Fatty Acids and Mitochondria;780 15.6.1;Lysosomal Storage Diseases;780 220.127.116.11;The cell contains specialized organelles for the recycling of waste material: the lysosomes;780 18.104.22.168;Deficiency of a lysosomal enzyme causes the blockage of the corresponding metabolic pathway, leading to the accumulation of its undigested substrate;781 22.214.171.124;For most lysosomal storage diseases, definitive cures are not available;782 126.96.36.199;Lysosomal storage disorders are pleiotropic, depending on the mutation, the enzyme affected and the sites of accumulated products;782 188.8.131.52.1;Farber disease;782 184.108.40.206.2;Gaucher disease;782 220.127.116.11.3;Krabbe disease (globoid cell leukodystrophy);783 18.104.22.168.4;Metachromatic leukodystrophy (MLD);783 22.214.171.124.5;Fabry disease;784 126.96.36.199.6;GM2 gangliosidoses (TaySachs disease; Sandhoff disease and GM2 activator deficiency);784 188.8.131.52.7;NiemannPick disease, types A and B;785 184.108.40.206.8;NiemannPick disease type C (NPC);785 220.127.116.11.9;The mucopolysaccharidoses (MPS);785 18.104.22.168.10;Neuronal ceroid lipofuscinoses (NCLs);785 15.6.2;Peroxisomal Diseases;785 22.214.171.124;Peroxisomes are specialized organelles for metabolism of oxygen peroxide and of various lipids;785 126.96.36.199;Peroxisomal dysfunction and the nervous system: peroxisomal defects impair the function of systemic organs and of the nervous system;786 15.6.3;Classification of Peroxisomal Diseases;786 188.8.131.52;Human diseases involving peroxisomal dysfunction were originally described as syndromes;786 184.108.40.206.1;Defects of peroxisomal biogenesis;786 220.127.116.11.2;Defects of single peroxisomal enzymes;786 15.6.4;Therapy of Peroxisomal Diseases;787 15.6.5;Diseases of Carbohydrate and Fatty Acid Metabolism;787 18.104.22.168;Diseases of carbohydrate and fatty acid metabolism in muscle;788 22.214.171.124.1;One class of glycogen or lipid metabolic disorders in muscle is manifest as acute, recurrent, reversible dysfunction;788 126.96.36.199.2;Phosphorylase deficiency (McArdle disea
se, glycogenosis type V) exemplifies the glycogenoses causing recurrent muscle energy crises, with cramps, myalgia;788 188.8.131.52.3;Genetic defects of phosphorylase b kinase (PHK);788 184.108.40.206.4;Other glycolytic defects involving PFK, PGK, PGAM, and LDH have clinical and pathological features similar to McArdle disease;789 220.127.116.11.5;CPT II deficiency has clinical features similar to McArdle disease;791 18.104.22.168.6;Other beta-oxidation defects have clinical features similar to McArdle disease;791 22.214.171.124.7;A second class of disorders of glucose and fatty acid metabolism causes progressive weakness;791 126.96.36.199.8;Acid maltase deficiency (AMD) (glycogenosis type II);791 188.8.131.52.9;Debrancher enzyme deficiency (glycogenosis type III, Coris disease, Forbe disease);792 184.108.40.206.10;Branching enzyme deficiency (glycogenosis type IV; Andersens disease);792 220.127.116.11.11;Carnitine deficiency;792 18.104.22.168.12;Defects in adipose triglyceride lipase (ATGL);793 22.214.171.124;The impairment of energy production, be it from carbohydrate or lipids, is expected to lead to common consequences and result in similar exercise-related signs and symptoms;793 126.96.36.199;Diseases of carbohydrate and fatty acid metabolism in brain;795 188.8.131.52.1;Defective transport of glucose across the bloodbrain barrier is caused by deficiency in the glucose transporter protein;795 184.108.40.206.2;One class of carbohydrate and fatty acid metabolism disorders is caused by defects in enzymes that function in the brain;795 220.127.116.11.3;Debrancher enzyme deficiency;795 18.104.22.168.4;Branching enzyme deficiency;795 22.214.171.124.5;Phosphoglycerate kinase deficiency;796 126.96.36.199.6;Lafora disease;796 188.8.131.52.7;Another class of carbohydrate and fatty acid metabolism disorders is caused by systemic metabolic defects that affect the brain. Glucose-6-phosphatase deficiency (glycogenosis type I, Von Gierke disease);796 184.108.40.206.8;Fructose-1,6-bisphosphatase deficiency;796 220.127.116.11.9;Phosphoenolpyruvate carboxykinase (PEPCK) deficiency;796 15.6
.5.3.10;Pyruvate carboxylase deficiency;796 18.104.22.168.11;Biotin-dependent syndromes;797 22.214.171.124.12;Glycogen synthetase deficiency;797 126.96.36.199.13;Fatty acid oxidation defects;797 15.6.6;Diseases of Mitochondrial Metabolism;797 188.8.131.52;Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system;797 184.108.40.206;Mitochondrial DNA is inherited maternally;798 220.127.116.11;The genetic classification of mitochondrial diseases divides them into three groups;799 18.104.22.168.1;Defects of nuclear DNA;799 22.214.171.124;Defects of communication between nDNA and mtDNA can also cause mitochondrial diseases;800 126.96.36.199.1;Defects in genes controlling mtDNA translation;800 188.8.131.52;The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism;800 184.108.40.206.1;Defects of mitochondrial transport;800 220.127.116.11.2;Defects of substrate utilization;800 18.104.22.168.3;Defects of the Krebs cycle;801 22.214.171.124.4;Defects of oxidationphosphorylation Coupling;801 126.96.36.199.5;Abnormalities of the respiratory chain;801 188.8.131.52.6;Abnormalities of the respiratory chain: defects of complex I;801 184.108.40.206.7;Abnormalities of the respiratory chain: defects of complex II;802 220.127.116.11.8;Abnormalities of the respiratory chain: coenzyme Q10 (CoQ10) deficiency;802 18.104.22.168.9;Abnormalities of the respiratory chain: defects of complex III;802 22.214.171.124.10;Abnormalities of the respiratory chain: defects of complex IV;802 126.96.36.199.11;Abnormalities of the respiratory chain: defects of complex V;803 15.6.7;Acknowledgments and Dedication;804 15.6.8;References;804 15.7;44. Disorders of Muscle Excitability;808 15.7.1;Organization of the Neuromuscular Junction;808 188.8.131.52;Nerve and muscle communicate through neuromuscular junctions;808 184.108.40.206;Acetylcholine acts as a chemical relay between the electrical potentials of nerve and muscle;810 220.127.116.11;The fidelity of signal transmission relies on the orchestration of innumerable stochastic molecular events;810
15.7.2;Excitation and Contraction of the Muscle Fiber;811 18.104.22.168;The excitable apparatus of muscle is composed of membranous compartments;811 22.214.171.124;Myofibrils are designed and positioned to produce movement and force;811 126.96.36.199;Calcium couples muscle membrane excitation to filament contraction;812 15.7.3;Genetic Disorders of the Neuromuscular Junction;814 188.8.131.52;Congenital myasthenic syndromes impair the operation of the acetylcholine receptor;814 184.108.40.206.1;ChAT Deficiency;814 220.127.116.11.2;AChR Deficiency;814 18.104.22.168.3;Rapsyn deficiency;815 22.214.171.124.4;Slow channel syndrome;815 126.96.36.199.5;Fast channel syndrome;815 188.8.131.52.6;Acetylcholinesterase deficiency;815 15.7.4;Hereditary Diseases of Muscle Membranes;815 184.108.40.206;Mutations of the sodium channel cause hyperkalemic periodic paralysis and paramyotonia congenital;815 220.127.116.11;Hypokalemic periodic paralysis is due to calcium channel mutations;816 18.104.22.168;Abnormal potassium channels in Andersen syndrome cause more than periodic paralysis;816 22.214.171.124;Ribonuclear inclusions are responsible for the multiple manifestations of myotonic dystrophy;816 126.96.36.199;Congenital myotonia is caused by mutant Cl- channels;817 188.8.131.52;Malignant hyperthermia caused by mutant ryanodine receptor calcium release channels;817 184.108.40.206;Calcium channel mutations may also cause malignant hyperthermia;818 220.127.116.11;Brody disease is an unusual disorder of the sarcoplasmic reticulum calcium ATPase;818 15.7.5;Immune Diseases of Muscle Excitability;818 18.104.22.168;Myasthenia gravis is caused by antibodies that promote premature AChR degradation;818 22.214.171.124;Antibodies against MuSK mimic myasthenia gravis;818 126.96.36.199;Antibodies cause calcium channel dysfunction in Lambert-Eaton syndrome;819 188.8.131.52;Potassium channel antibodies in Isaac syndrome cause neuromyotonia;819 15.7.6;Toxins and Metabolites that Alter Muscular Excitation;820 184.108.40.206;Bacterial botulinum toxin blocks presynaptic ACh release;820 220.127.116.11;Snake, scorpion, spider, fis
h and snail peptide venoms act on multiple molecular targets at the neuromuscular junction;821 18.104.22.168;Electrolyte imbalances alter the voltage sensitivity of muscle ion channels;823 15.7.7;References;824 15.8;45. Motor Neuron Diseases;826 15.8.1;Amyotrophic Lateral Sclerosis Is the Most Common Adult-Onset Motor Neuron Disease;826 22.214.171.124;The disease is characterized clinically by weakness, muscle atrophy and spasticity affecting both upper and lower motor neurons;827 126.96.36.199;Although most cases ALS are sporadic, mutations in several genes may cause familial ALS;828 188.8.131.52.1;ALS1 is caused by mutant SOD1;828 184.108.40.206.2;ALS2 is linked to mutant Alsin;828 220.127.116.11.3;ALS4 is linked to mutations in a helicase gene;828 18.104.22.168.4;Angiogenic factors may be linked to ALS;828 22.214.171.124.5;Mutant dynactin p150Glued causes fALS;829 126.96.36.199.6;VAPB associated with ALS is a ligand for eph receptors;829 188.8.131.52.7;ALS is linked to two genes involved in RNA metabolism: TDP-43 and FUS;829 184.108.40.206.8;Mutations in OPTN were identified in several japanese patients with ALS;830 220.127.116.11.9;Identification of valosin-containing protein (VCP) is linked to fALS by exome sequencing;831 15.8.2;Models of Motor Neuron Disease Induced by Experimental Nerve Injury Have been Instructive;831 18.104.22.168;Interrupting the communication between the motor neuron cell body and axon by transection, crush or avulsion induces motor neuron injury;831 22.214.171.124;IDPN induces neurofilamentous axonal pathology;831 15.8.3;Selected Genetic Models of Relevance to ALS and Other Motor Neuron Diseases Have been Identified or Generated;831 126.96.36.199;Hereditary canine spinal muscular atrophy (HCSMA) is a naturally occurring mutation that produces motor neuron disease;831 188.8.131.52;Some transgenic mice expressing wild-type or mutant NF genes develop motor neuron disease and neurofibrillary pathology;832 184.108.40.206;fALS-linked mutant SOD1 mice reproduce many of the clinical and pathological features of ALS;832 220.127.116.11;Lines
of mice harboring other mutant genes may also develop an ALS-like phenotype;832 18.104.22.168.1;Mutant dynactin p150glued transgenic mice have MND-like pathology;833 22.214.171.124.2;Mutant tubulin-specific chaperone E transgenic mice exhibit progressive motor neuropathy;833 126.96.36.199.3;To test the role of NF in mutant SOD1 mice, the latter animals were crossbred to several lines of mice that have altered distributions of NF;833 188.8.131.52.4;Vascular endothelial growth factor (VEGF) influences the growth and permeability of blood vessels;833 184.108.40.206;The molecular mechanisms whereby mutant SOD1 causes selective motor neuron death have yet to be defined;833 220.127.116.11.1;Is the toxicity of mutated SOD1 cell-autonomous?;833 18.104.22.168.2;Expression of GLT1 is implicated as a possible cofactor;833 22.214.171.124.3;Mutation-induced conformational effects and copper oxidative toxicity have been implicated;834 126.96.36.199.4;Accumulating evidence supports the view that fALS-associated mutants facilitate misfolding of wild-type SOD1;834 188.8.131.52;A variety of experimental therapeutic strategies have been tested in mutant SOD1 transgenic mice;834 15.8.4;Available Genetic Mouse Models Will Aid in Discovering Disease Mechanisms and Novel Means of Therapy;834 15.8.5;Acknowledgments;836 15.8.6;References;836 15.9;46. Neurobiology of Alzheimers Disease;840 15.9.1;Alzheimers Disease is the Most Prevalent Neurodegenerative Disease of the Elderly;840 184.108.40.206;The clinical syndrome, ranging from mild cognitive impairments to severe dementia, reflects biochemical and cellular abnormalities in specific regions and circuits in the brain;841 220.127.116.11;Advances in laboratory measurements and imaging are of value in establishing the diagnosis of AD;841 18.104.22.168;Familial forms of AD are associated with mutations in select genes inherited as autosomal dominants, while variants in other genes can lead to increased risk of sporadic AD;842 22.214.171.124.1;APP Mutations are Linked to fAD;842 126.96.36.199.2;Mutations in PS1 and PS2 ar
e Linked to fAD;842 188.8.131.52;Multiple neurotransmitter circuits and brain networks are damaged in AD;842 184.108.40.206;Neuritic plaques, one of the pathological hallmarks of AD, are composed of swollen neurites, extracellular deposits of Aß 40-42 peptides derived from;843 220.127.116.11;Neurofibrillary tangles (NFT), another characteristic feature of AD, are composed of intracellular bundles of paired helical filaments (PHF), which represent;843 18.104.22.168;Aspartyl proteases carry out the ß- and g-secretase cleavages of APP to generate Aß peptides;844 22.214.171.124;Transgenic strategies have been used to create models of Aß amyloidosis and tauopathies;845 126.96.36.199;Gene targeting approaches have identified and validated targets for therapy;846 188.8.131.52;Transgenic mouse models are being used to test a variety of novel therapies;847 15.9.2;Conclusions;848 15.9.3;Acknowledgments;850 15.9.4;References;850 15.10;47. Synucleinopathies and Tauopathies;854 15.10.1;Introduction;854 15.10.2;Synucleins;855 184.108.40.206;The human synuclein family consists of three members;855 220.127.116.11;Synucleins are lipid-binding proteins;855 15.10.3;Parkinsons Disease and Other Lewy Body Diseases;856 18.104.22.168;SNCA mutations cause familial Parkinsons disease;856 22.214.171.124;Lewy body filaments are made of a-synuclein;856 126.96.36.199;The development of a-synuclein pathology is not random;857 188.8.131.52;Other genes are implicated in Parkinsons disease;857 15.10.4;Multiple System Atrophy;858 15.10.5;Synthetic a-Synuclein Filaments;858 15.10.6;Animal Models of Synucleinopathies;858 184.108.40.206;Rodents and primates;858 220.127.116.11;Flies, worms and yeasts;859 15.10.7;SynucleinopathiesOutlook;859 15.10.8;Microtubule-Associated Protein Tau;859 18.104.22.168;Six tau isoforms are expressed in adult human brain;859 22.214.171.124;Tau is a phosphoprotein;860 15.10.9;Tau and Alzheimers Disease;860 126.96.36.199;The paired helical filament is made of tau protein;860 188.8.131.52;Filamentous tau is hyperphosphorylated;860 184.108.40.206;The development of t
au pathology is not random;861 15.10.10;Other Tauopathies;861 220.127.116.11;Other taupathies include progressive supranuclear palsy, corticobasal degeneration and Picks disease;861 15.10.11;MAPT Mutations Causing Tauopathy;861 18.104.22.168;FTD is characterized by atrophy of the frontal and temporal lobes of the cerebral cortex, with additional subcortical changes;861 22.214.171.124;MAPT mutations are exonic or intronic;861 15.10.12;Relevance for Other Tauopathies;862 15.10.13;Synthetic Tau Filaments;863 15.10.14;Animal Models of Human Tauopathies;863 126.96.36.199;Rodents and fish;863 188.8.131.52;Flies, worms and yeasts;865 15.10.15;TauopathiesOutlook;866 15.10.16;References;866 15.11;48. Cellular and Molecular Basis of Neurodegeneration in the CAGPolyglutamine Repeat Diseases;869 15.11.1;Introduction to the CAGPolyglutamine Repeat Diseases;869 184.108.40.206;CAG repeat expansions are responsible for nine inherited neurodegenerative disorders;869 220.127.116.11;Normal functions of polyglutamine disease proteins;870 15.11.2;Expanded Polyglutamine Tracts Promote Protein Misfolding to Drive Neurotoxicity;870 18.104.22.168;Disease-length polyglutamine tracts adopt a novel, toxic conformation;870 22.214.171.124;Polyglutamine disease proteins form aggregates visible at the light microscope level;870 126.96.36.199;Polyglutamine disease proteins exist as misfolded monomers, oligomers and protofibrils;871 188.8.131.52;What is the toxic misfolded protein species in the polyglutamine repeat diseases?;871 15.11.3;The Role of Protein turnover Pathways in Polyglutamine Disease Pathogenesis;871 184.108.40.206;Are polyglutamine tracts substrates for the ubiquitin-proteasome system and autophagy pathways?;871 220.127.116.11;Autophagy pathway involvement in polyglutamine neurodegeneration;872 18.104.22.168;Evidence for autophagy dysfunction in the polyglutamine repeat diseases;874 15.11.4;The Importance of Normal Function in the Polyglutamine Repeat Diseases;874 22.214.171.124;Interference with ataxin-7s function as a transcription regulato
ry protein in SCA7;874 126.96.36.199;Ataxin-1 protein complex associations account for SCA1 disease pathogenesis;874 188.8.131.52;Post-translational modifications as determinants of disease;874 184.108.40.206;Phosphorylation;874 220.127.116.11;Acetylation;875 18.104.22.168;Sumoylation;875 15.11.5;RNA Toxicity in the Polyglutamine Repeat Diseases?;875 15.11.6;Gene Silencing is a Promising Therapy for Polyglutamine Repeat Disease;875 22.214.171.124;RNA interference knock-down and antisense oligonucleotide knock-down: two approaches;875 126.96.36.199;Indiscriminate gene silencing;876 188.8.131.52;Allele-specific silencing;876 15.11.7;References;878 15.12;49. Neurotransmitters and Disorders of the Basal Ganglia;881 15.12.1;Anatomy and Physiology of the Basal Ganglia;881 184.108.40.206;The basal ganglia are components of larger circuits;881 220.127.116.11;Involvement of the basal ganglia in movement control;882 18.104.22.168;Multiple neurotransmitter systems are found in the basal ganglia;882 22.214.171.124.1;GABA;882 126.96.36.199.2;Glutamate;883 188.8.131.52.3;Acetylcholine;883 184.108.40.206.4;Dopamine;884 220.127.116.11.5;Dopamineacetylcholine balance;885 18.104.22.168;Adenosine, cannabinoid and neuropeptides function in the basal ganglia;885 15.12.2;Disorders that Involve Basal Ganglia Dysfunction;886 22.214.171.124;Parkinsons disease is a hypokinetic movement disorder;886 126.96.36.199.1;Pathology;886 188.8.131.52.2;Etiology;886 184.108.40.206.3;Animal models;887 220.127.116.11.4;Pathophysiology;887 18.104.22.168.5;Symptomatic drug treatment of PD;888 22.214.171.124.6;Surgical therapy;889 126.96.36.199.7;Neuroprotective treatment of PD;889 188.8.131.52;Huntingtons disease is a hyperkinetic movement disorder;890 184.108.40.206.1;Genetic and molecular aspects;890 220.127.116.11.2;Animal models;890 18.104.22.168.3;Treatment;890 22.214.171.124;Dystonia is a disorder with involuntary movements;891 126.96.36.199.1;Etiology and classification;891 188.8.131.52.2;Pathophysiology;892 184.108.40.206.3;Treatment;892 220.127.116.11;Neuropsychiatric disorders;892 18.104.22.168;Drugs affecting the basal ganglia;893 22.214.171.124.1;
Dopamine depleting agents;893 126.96.36.199.2;Dopamine receptor blocking agents;893 188.8.131.52.3;Tardive syndromes;893 15.12.3;Conclusion;893 15.12.4;References;895 15.13;50. Molecular Basis of Prion Diseases;897 15.13.1;Introduction;898 15.13.2;Prion Diseases are Biologically Unique;898 184.108.40.206;Discovery of the prion protein;898 220.127.116.11;Prion protein is encoded by the host;898 18.104.22.168;Aberrant metabolism of the prion protein is the central feature of prion disease;898 15.13.3;Animal Prion Diseases;898 22.214.171.124;Scrapie and BSE;898 126.96.36.199;Other animal prion diseases;899 15.13.4;Human Prion Diseases;899 188.8.131.52;Human prion disease most commonly presents itself sporadically;899 184.108.40.206;Pathogenic mutations in the prion protein gene cause inherited prion disease;899 220.127.116.11;Acquired human prion diseases include kuru and variant CJD;900 18.104.22.168;Prion protein polymorphism contributes genetic susceptibility to prion disease;900 22.214.171.124;Human prion diseases are clinically heterogeneous;900 15.13.5;Prion Disease Pathology and Pathogenesis;901 126.96.36.199;Peripheral pathogenesis involves the lymphoreticular system;901 188.8.131.52;Prion disease produces characteristic pathology in the central nervous system;901 15.13.6;The Protein-Only Hypothesis of Prion Propagation;902 184.108.40.206;Prion propagation involves conversion of PrPC to PrPSc;902 15.13.7;Characterization of PrPC;902 220.127.116.11;PrPC has a predominantly alpha-helical conformation;902 18.104.22.168;Reverse genetics approaches to studying PrPC;903 22.214.171.124;The function of PrPC remains unknown;903 126.96.36.199;PrP knockout mice have subtle abnormalities;903 15.13.8;Characterization of PrPSc;904 188.8.131.52;PrPSc has a predominantly beta-sheet conformation;904 184.108.40.206;Prion structure remains unknown;904 220.127.116.11;In vitro generation of alternative PrP conformations and prion infectivity;905 15.13.9;The Molecular Basis of Prion Strain Diversity;905 18.104.22.168;Prion strain diversity appears to be encoded by PrP itself;905
22.214.171.124;Distinct PrPSc types are seen in human prion disease;905 126.96.36.199;Difficulties in defining human prion strains;906 15.13.10;Prion Transmission Barriers;907 188.8.131.52;Prion transmission between species is limited by a barrier;907 184.108.40.206;Both PrP sequence and prion strain type influence prion transmission barriers;907 220.127.116.11;A conformational selection model of prion transmission barriers;907 18.104.22.168;Subclinical forms of prion disease pose a risk to public health;907 22.214.171.124;The mechanism of prion-mediated neurodegeneration is unknown;908 15.13.11;Future Perspectives;908 15.13.12;References;909 16;VII. SENSORY TRANSDUCTION;912 16.1;51. Molecular Biology of Vision;914 16.1.1;Structure and Development of the Visual System;914 126.96.36.199;The visual system is composed of unique structures optimized for collection, detection and processing of visual information;914 188.8.131.52;The retina is composed of highly organized neuronal sublayers;915 184.108.40.206;The ganglion cell axons of the optic nerve carry visual signals from the retina to the brain;915 220.127.116.11;The eye develops as an outcropping of the developing brain;916 16.1.2;Photoreceptors and Phototransduction;917 18.104.22.168;Photoreceptors are polarized cells, with specialized primary cilia, outer segments, devoted to phototransduction;917 22.214.171.124;Phototransduction consists of a highly amplified cascade of light-triggered changes in protein conformation, and changes in interactions of proteins with one another and with;917 126.96.36.199;Recovery of the dark current after light stimulation is a multistep process mediated by Ca2+ and proteins exerting negative regulation;919 188.8.131.52;Cone phototransduction uses mechanisms and molecules similar to those in rods, but is optimized for speed rather than sensitivity;920 16.1.3;Signaling Downstream of Photoreceptors;922 184.108.40.206;Secondary neurons respond to changes in glutamate release by rods and cones;922 220.127.116.11;ON and OFF bipolar cells use different types of rece
ptors and response mechanisms;922 18.104.22.168;Cone bipolar cells signal to ganglion cells, and rod bipolar cells signal to aii amacrine cells;922 16.1.4;Recycling of Phototransduction Molecules;923 22.214.171.124;Rhodopsin regeneration requires a complex series of enzyme-catalyzed reactions in photoreceptors and RPE;923 126.96.36.199;Cones use a visual cycle distinct from that of rods to regenerate pigments;924 188.8.131.52;Retinal pigemented epithelial (RPE) cells promote disk membrane turnover by phagocytosis;924 16.1.5;Retinal Neurodegeneration;924 184.108.40.206;Defects in genes essential for functions of photoreceptors cause retinal degeneration;924 220.127.116.11;Age-related macular degeneration is emerging as the most common blinding disease of the developed world;924 16.1.6;References;925 16.2;52. Molecular Basis of Olfaction and Taste;929 16.2.1;Olfaction;929 18.104.22.168;The mammalian olfactory system possesses enormous discriminatory power;929 22.214.171.124;The initial events in olfaction occur in a specialized olfactory neuroepithelium;930 126.96.36.199;The identification and cloning of genes encoding odorant receptors helped to reveal organizational principles of odor coding;930 188.8.131.52;Odor discrimination involves a very large number of different odorant receptors, each responsive to a small set of odorants;931 184.108.40.206;The information generated by hundreds of different receptor types must be organized to achieve a high level of olfactory discrimination;931 220.127.116.11.1;Zonal Expression of Olfactory Receptors;932 18.104.22.168.2;Convergence of Sensory Neurons Onto a few Glomeruli in the Olfactory Bulb;932 22.214.171.124;The sensitivity of the olfactory system is likely to derive from the capacity of the olfactory transduction apparatus to effectively amplify and rapidly terminate signals;932 126.96.36.199;Odorant recognition initiates a second-messenger cascade leading to the depolarization of the neuron and the generation of action potentials;932 188.8.131.52;Negative feedback processes mediate adaptation of the ol
factory transduction apparatus to prolonged or repetitive stimulation;933 184.108.40.206;Subpopulations of OSNs use alternative olfactory transduction mechanisms;934 220.127.116.11;The vomeronasal organ is an accessory chemosensing system that plays a major role in the detection of semiochemicals;935 18.104.22.168;Most vomeronasal sensory neurons are narrowly tuned to specific chemical cues, and utilize a unique mechanism of sensory transduction;936 16.2.2;Taste;936 22.214.171.124;Multiple senses, including taste, contribute to our total perception of food;936 126.96.36.199;Taste receptor cells are organized into taste buds;937 188.8.131.52;Sensory afferents within three cranial nerves innervate the taste buds;937 184.108.40.206;Sweet, bitter and umami taste involve G protein-coupled receptors;937 220.127.116.11.1;Type 1 Taste Receptors (T1Rs) Recognize Sweet and Umami Stimuli;937 18.104.22.168.2;Type 2 Taste Receptors (T2Rs) Mediate Responses to Bitter-Tasting Stimuli;938 22.214.171.124.3;T1Rs and T2Rs also Have Important Functions Outside the Gustatory System;938 126.96.36.199;Sweet, bitter and umami tasting stimuli are transduced by a G-proteincoupled signaling cascade;938 188.8.131.52;Salts and acids are transduced by direct interaction with ion channels;939 16.2.3;Acknowledgments;939 16.2.4;References;939 16.3;53. Molecular Biology of Hearing and Balance;941 16.3.1;General Features of Mechanotransduction;941 184.108.40.206;Mechanotransduction is of great utility for all organisms;941 220.127.116.11;Models for mechanotransduction allow comparison of mechanoreceptors from many organisms and cell types;941 16.3.2;Non-Vertebrate Model Systems;942 18.104.22.168;Worm mechanoreceptors use a transduction cascade that depends on epithelial sodium channels (ENaC);943 22.214.171.124;Fly mechanoreceptors use molecules similar to those of hair cells;943 16.3.3;Hair Cells;943 126.96.36.199;Hair cells are the sensory cells of the auditory and vestibular systems;943 188.8.131.52;Hair cells are exposed to unusual extracellular fluids and potentials;944 184.108.40.206;Mechanic
al transduction depends on activation of ion channels linked to extracellular and intracellular structures;945 220.127.116.11;Some of the molecules responsible for transduction have been identified;946 18.104.22.168;Other hair cell molecules control stereocilia actin;946 16.3.4;Hair Cells in the Inner Ear;948 16.3.5;Balance: Vestibular Organs;948 22.214.171.124;Vestibular organs detect head rotation and linear acceleration;948 126.96.36.199;Hair bundles display varying morphology and physiology;948 16.3.6;Hearing: Cochlea;948 188.8.131.52;The cochlea detects sound and is tonotopically organized;948 184.108.40.206;High-frequency sound detection requires specialized structures and molecules;950 220.127.116.11;Cochlear hair cell mechanotransduction is similar to that of vestibular hair cells;951 16.3.7;Conclusions;951 16.3.8;References;951 16.4;54. Pain;953 16.4.1;Nociceptive Versus Clinical Pain;953 16.4.2;Nociceptors are First Responders;954 18.104.22.168;Primary sensory neurons are located in the dorsal root ganglions (DRG) of spinal nerves and the semilunar ganglions of the trigeminal nerves;954 22.214.171.124;Receptor profiles define the response modalities of nociceptors;954 126.96.36.199;Voltage-gated sodium channels determine the conduction of noxious information from the periphery to the spinal cord;955 16.4.3;Pain Transmission in the Spinal Cord;955 188.8.131.52;Nociceptive information enters the dorsal horn of the spinal cord;955 184.108.40.206;Signals are modulated by spinal interneurons;955 16.4.4;Brainstem, Thalamus and Cortex;956 220.127.116.11;Nuclei in the brainstem and thalamus, and distinct cortical areas are the major projection targets for nociceptive information;956 18.104.22.168;Brainstem nuclei play a major role in the modulation of pain;958 16.4.5;Opioid Analgesia;958 16.4.6;Cannabinoids;958 16.4.7;Inflammatory Pain;959 22.214.171.124;Tissue injury produces an inflammatory soup of signaling molecules;959 126.96.36.199;Molecular mechanisms involved in peripheral sensitization;959 188.8.131.52;Central sensitization;959 184.108.40.206;Prolon
ged homosynaptic facilitation;960 16.4.8;Neuropathic Pain;961 220.127.116.11;Paradoxically, nervous system injury may produce not only sensory loss but also chronic pain;961 18.104.22.168;Spontaneous discharges and enhanced excitability of sensory neurons;961 22.214.171.124;Allodynia signals a crossover of sensory modalities;961 126.96.36.199;Central sensitization and descending facilitation;962 188.8.131.52;Disinhibition;962 184.108.40.206;Immune response to nerve injury;963 16.4.9;Genetic Factors;964 220.127.116.11;Nociceptive responses and the susceptibility to clinical pain depend on genetic factors;964 16.4.10;Conclusion;964 16.4.11;Acknowledgments;964 16.4.12;References;965 17;VIII. NEURAL PROCESSING AND BEHAVIOR;968 17.1;55. Endocrine Effects on the Brain and Their Relationship to Behavior;970 17.1.1;Introduction;970 17.1.2;Behavioral Control of Hormonal Secretion;971 18.104.22.168;The hypothalamic releasing factors regulate release of the anterior pituitary trophic hormones;971 22.214.171.124;Secretion of pituitary hormones is responsive to behavior and effects of experience;971 126.96.36.199;Hormones secreted in response to behavioral signals act in turn on the brain and on other tissues;971 17.1.3;Classification of Hormonal Effects;972 188.8.131.52;Hormonal actions on target neurons are classified in terms of cellular mechanisms of action;972 17.1.4;Biochemistry of Steroid and Thyroid Hormone Actions;974 184.108.40.206;Steroid hormones are divided into six classes, based on physiological effects: estrogens, androgens, progestins, glucocorticoids, mineralocorticoids and vitamin D;974 220.127.116.11;Some steroid hormones are converted in the brain to more active products that interact with receptors;974 18.104.22.168.1;The Aromatization of Testosterone;975 22.214.171.124.2;Vitamin D;976 126.96.36.199;Genomic receptors for steroid hormones have been clearly identified in the nervous system;976 17.1.5;Intracellular Steroid Receptors: Properties and Topography;978 188.8.131.52;Steroid hormone receptors are phosphoproteins that have a DNA-binding dom
ain and a steroid-binding domain;978 184.108.40.206.1;Estradiol;978 220.127.116.11.2;Progesterone;978 18.104.22.168.3;Androgen;979 22.214.171.124.4;Glucocorticoid;979 126.96.36.199.5;Mineralocorticoid;979 188.8.131.52.6;Vitamin D;979 17.1.6;Membrane Steroid Receptors and Signaling Pathways;979 17.1.7;Biochemistry of Thyroid Hormone Actions on Brain;980 17.1.8;Diversity of Steroid-Hormone Actions on the Brain;981 184.108.40.206;During development, steroid-hormone receptors become evident in target neurons of the brain;981 220.127.116.11;The response of neural tissue to damage involves some degree of structural plasticity, as in development;982 18.104.22.168;Activation and adaptation behaviors may be mediated by hormones;982 22.214.171.124;Enhancement of neuronal atrophy and cell loss during aging by severe and prolonged psychosocial stress are examples of allostatic load;985 17.1.9;SUMMARY;986 17.1.10;References;986 17.2;56. Learning and Memory;988 17.2.1;Brief History of Memory Research in Humans;988 126.96.36.199;The Penfield studies;989 188.8.131.52;Amnesia patients and the role of the temporal lobe in memory;989 17.2.2;Divisions of Memory;990 184.108.40.206;Declarative memory vs. procedural memory;990 220.127.116.11;Short-term memory vs. long-term memory;990 17.2.3;Molecular Mechanisms of Learning;990 18.104.22.168;Hebbs rule and experimental models for synaptic plasticity;990 22.214.171.124;The NMDA receptor and LTP induction;991 126.96.36.199;Molecular mechanisms underlying the early- and late-phase expressions of LTP;992 188.8.131.52;Other forms of synaptic plasticity: Long-term depression (LTD) and NMDA receptor-independent LTP;993 184.108.40.206;Doogie mice: a smart way to validate Hebbs rule for learning and memory;994 17.2.4;Molecular Mechanisms of Memory Consolidation and Storage;996 220.127.116.11;Retrograde amnesia and post-learning consolidation by the hippocampus;996 17.2.5;Neural Population-Level Memory Traces and Their Organizing Principles;996 18.104.22.168;In search of memorys neural code;996 22.214.171.124;Visualizing network-level real-time memory traces;999 17.
2.5.3;Identification of neural cliques as real-time memory coding units;999 126.96.36.199;General-to-specific feature-encoding neural clique assemblies;999 188.8.131.52;Concept cells in the hippocampus: nest cells and Halle Berry cells;1000 184.108.40.206;Differential reactivations within episodic cell assemblies underlying selective memory consolidation;1000 220.127.116.11;The generalization function of the hippocampus;1002 18.104.22.168;Imagination of the hippocampus;1003 17.2.6;References;1004 17.3;57. The Neurochemistry of Sleep and Wakefulness;1007 17.3.1;Sleep Phenomenology and Function: The Search for Neurochemical Substrates;1008 22.214.171.124;The daily cycle of sleep and wakefulness is one of the most fundamental aspects of human biology;1008 126.96.36.199;The functions of sleep remain enigmatic;1008 188.8.131.52;There are more neurotransmitters that promote wakefulness than those that produce sleep;1009 17.3.2;Development of Sleep Disorders Medicine and Sleep Neurobiology;1009 184.108.40.206;Compared to other medical specialties, sleep disorders medicine has a very short history;1009 220.127.116.11;Understanding the neurochemical regulation of sleep is essential for advancing sleep disorders medicine;1010 17.3.3;Monoamines;1011 18.104.22.168;Serotonin, norepinephrine and histamine are major components of the ascending reticular activating system, and each of these neurotransmitters plays a unique role in;1011 22.214.171.124;Norepinephrine promotes arousal during normal wakefulness, and augments arousal during periods of stress and in response to psychostimulant drugs;1011 126.96.36.199;Serotonin has a biphasic effect on sleep;1011 188.8.131.52;Histamine levels are greater during wakefulness than during sleep, consistent with the fastest firing rates of histamine-containing neurons occurring during wakefulness;1012 184.108.40.206;Sleep disorders and depression are linked by monoamines;1012 17.3.4;Acetylcholine;1012 220.127.116.11;Acetylcholine contributes significantly to the generation of REM sleep and wakefulness;1012 18.104.22.168;Evidence t
hat pontine cholinergic neurotransmission promotes the generation of REM sleep comes from many studies using a wide range of approaches;1013 22.214.171.124;Acetylcholine, depression, REM sleep and pain;1013 17.3.5;Dopamine;1013 126.96.36.199;Unlike other monoaminergic neurons, dopaminergic cells do not cease firing during REM sleep;1013 188.8.131.52;Restless legs syndrome, Parkinsons disease and sleep;1014 17.3.6;Hypocretins/Orexins;1014 184.108.40.206;The discovery of hypocretins (orexins) provides an excellent example of how preclinical studies using animal models provided powerful tools for gaining mechanistic insights into;1014 220.127.116.11;Hypocretins promote normal wakefulness;1015 18.104.22.168;Loss of hypocretinergic neurons underlies the human sleep disorder narcolepsy and contributes to other neurological disorders that show sleep;1015 17.3.7;Amino Acids;1015 22.214.171.124;γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and drugs that enhance transmission at GABAA;1015 126.96.36.199;The effects of GABA on sleep and wakefulness vary as a function of brain region;1016 188.8.131.52;GABAergic transmission in the pontine reticular formation contributes to the regulation of sleep and wakefulness;1016 184.108.40.206;Clinical implications of GABAergic transmission for sleep;1016 220.127.116.11;Glutamate is the major excitatory neurotransmitter in the brain, yet elucidating the role of glutamate in regulating sleep and wakefulness has been challenging;1016 18.104.22.168;Effects of glutamate on sleep and wakefulness vary as a function of brain region;1017 22.214.171.124;Glutamate modulates the interaction between sleep, depression and pain;1017 17.3.8;Adenosine;1018 126.96.36.199;Adenosine is an endogenous sleep factor that mediates the homeostatic drive to sleep;1018 188.8.131.52;Adenosine inhibits wakefulness and promotes sleep via multiple mechanisms;1018 184.108.40.206;Adenosine is a link between opioid-induced sleep disruption and pain;1018 17.3.9;Conclusions and Future Directions;1019 17.3.10;Reference
s;1021 17.4;58. The Neurochemistry of Schizophrenia;1025 17.4.1;Clinical Aspects of Schizophrenia;1025 220.127.116.11;Schizophrenia is a severe, chronic disabling mental disorder;1025 18.104.22.168;Schizophrenia is characterized by three independent symptom clusters;1026 22.214.171.124;Schizophrenia is a disorder of complex genetics;1026 126.96.36.199;Current treatment of schizophrenia relies on atypical antipsychotic drugs;1026 17.4.2;Brain Imaging;1028 188.8.131.52;Brain imaging studies provide unequivocal evidence that schizophrenia is a brain disease;1028 184.108.40.206;Functional imaging studies have consistently shown corticolimbic abnormalities in schizophrenia;1028 17.4.3;Cellular and Molecular Studies;1029 220.127.116.11;The dopamine hypothesis has dominated schizophrenia research for 40 years;1029 18.104.22.168;Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia;1030 22.214.171.124;GABAergic neurons are also implicated in schizophrenia;1032 126.96.36.199;The cholinergic system has also been implicated in schizophrenia;1033 188.8.131.52;Some intracellular signal transduction molecules are reduced in schizophrenia;1033 184.108.40.206;Proteins involved in fundamental structure and function of neurons are decreased in schizophrenia;1033 220.127.116.11;Glia may play a role in schizophrenia;1033 17.4.4;Summary;1034 17.4.5;References;1035 17.5;59. The Neurochemistry of Autism;1037 17.5.1;Clinical Aspects of Autism Spectrum Disorders (ASDs);1037 18.104.22.168;ASDs are defined by three independent symptom clusters;1037 22.214.171.124;Autism is heterogeneous from a behavioral, neurobiological and genetic standpoint;1038 126.96.36.199;The autism field is moving towards a more dimensional and less categorical perspective;1038 188.8.131.52;Current pharmacological treatment of autism is usually effective for only certain aspects of the symptom constellation;1039 17.5.2;Genetic Studies;1039 184.108.40.206;The genetics of autism are complex, heterogenetic and, in most cases, polygenetic;1039 220.127.116.11;Roles of epistasis and emergenesis
are unclear;1039 17.5.3;Neurochemical Studies;1039 18.104.22.168;Limited postmortem brain data are available and are not definitive;1039 22.214.171.124;Dopaminergic functioning appears normal;1040 126.96.36.199;Stress response systems: basal functioning is normal, but hyperreactive in autism;1040 188.8.131.52;The serotonin system: a focus on platelet hyperserotonemia and the 5-HT2 receptor;1040 184.108.40.206;Decreased production of melatonin in autism has been reported and focuses attention on circadian processes;1041 17.5.4;Conclusion;1041 17.5.5;References;1043 17.6;60. Neurobiology of Severe Mood and Anxiety Disorders;1046 17.6.1;Mood Disorders;1046 17.6.2;Neurotransmitter and Neuropeptide Systems and the Pathophysiology of Mood Disorders;1047 220.127.116.11;Serotonergic system;1047 18.104.22.168;Noradrenergic system;1048 22.214.171.124;Dopaminergic system;1049 126.96.36.199;Cholinergic system;1049 188.8.131.52;Glutamatergic system;1049 184.108.40.206;GABAergic system;1049 220.127.116.11;Cortical-hypothalamic-pituitary-adrenal axis;1049 18.104.22.168;Thyroid axis;1049 22.214.171.124;Other neuropeptides;1050 126.96.36.199;Brain growth factors;1050 188.8.131.52;Substance P;1050 17.6.3;Neuroanatomical and Neuropathological Correlates of Mood Disorders;1050 184.108.40.206;Functional neuroimaging methods;1050 220.127.116.11;Stress, glucocorticoids and neuroplasticity;1051 17.6.4;Intracellular Signaling Pathways;1051 18.104.22.168;The G-proteinsubunit/cyclic adenosine monophosphate (CAMP)generating signaling pathway;1052 22.214.171.124;The protein kinase C signaling pathway;1052 126.96.36.199;Glycogen synthase kinase;1052 188.8.131.52;BDNF and Bcl-2;1054 184.108.40.206;Intracellular calcium signaling;1054 17.6.5;Anxiety Disorders;1055 17.6.6;The Neurochemistry of Fear and Anxiety;1055 220.127.116.11;Noradrenergic systems;1055 18.104.22.168;Serotonergic system;1056 22.214.171.124;GABAergic system;1056 126.96.36.199.1;CRH and stress axes;1057 188.8.131.52;Other neuropeptides;1057 184.108.40.206.1;Neuropeptide Y;1057 220.127.116.11.2;Cholecystokinin;1057 18.104.22.168.3;Substance P;1058 17.6.7;Intracellular Targets for Anxiety Di
sorders;1058 17.6.8;Future Directions and the Development of Novel Therapeutics;1058 17.6.9;References;1059 17.7;61. Addiction;1062 17.7.1;General Principles;1063 22.214.171.124;Addiction is characterized by compulsive drug use, despite severe negative consequences;1063 126.96.36.199;Many forces may drive compulsive drug use;1063 17.7.2;Neuronal Circuitry of Addiction;1063 188.8.131.52;Natural reinforcers and drugs of abuse increase dopamine transmission;1063 184.108.40.206;Many neuronal circuits are ultimately involved in addiction;1065 17.7.3;Opiates;1066 220.127.116.11;Opiates are drugs derived from opium, including morphine and heroin;1066 18.104.22.168;There are three classical opioid receptor types;1066 22.214.171.124;Opioid receptors generally mediate neuronal inhibition;1066 126.96.36.199;Chronic opiate treatment results in complex adaptations in opioid receptor signaling;1066 188.8.131.52;Opiate addiction involves multiple neuronal systems;1066 184.108.40.206;Upregulation of the cyclic AMP (cAMP) second-messenger pathway is a well-established molecular adaptation;1067 220.127.116.11;There are two main treatments for the opiate withdrawal syndrome;1068 18.104.22.168;Endogenous opioid systems are an integral part of the reward circuitry;1068 17.7.4;Psychomotor Stimulants;1068 22.214.171.124;This drug class includes cocaine and amphetamine derivatives;1068 126.96.36.199;Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants;1068 188.8.131.52;Cocaine and amphetamines initiate neuronal adaptations by repeatedly elevating monoamine levels but ultimately affect glutamate and other transmitter systems;1069 184.108.40.206;Dopamine receptor transmission involves multiple signaling cascades and is altered in psychomotor stimulant addiction;1070 17.7.5;Cannabinoids (Marijuana);1070 220.127.116.11;Marijuana and hashish are derivatives of the cannabis sativa plant;1070 18.104.22.168;Cannabinoid effects in the CNS are mediated by the CB1 receptor;1070 22.214.171.124;Endocannabinoids are endogenous liga
nds for the CB1 receptor;1071 126.96.36.199;Endocannabinoids serve as retrograde messengers that regulate synaptic plasticity;1071 188.8.131.52;There are many similarities between endogenous opioid and cannabinoid systems;1073 17.7.6;Nicotine;1073 184.108.40.206;Nicotine is responsible for the highly addictive properties of tobacco products;1073 220.127.116.11;Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR);1073 18.104.22.168;The ventral tegmental area (VTA) is a critical site for nicotine action;1073 17.7.7;Ethanol, Sedatives and Anxiolytics;1074 22.214.171.124;Alcoholism is a chronic relapsing disorder;1074 126.96.36.199;Ethanol interacts directly with ligand-gated and voltage-gated ion channels;1074 188.8.131.52;Multiple neuronal systems contribute to the reinforcing effects of ethanol;1074 184.108.40.206;Pharmacotherapies for alcoholism are improving;1074 220.127.116.11;Barbiturates and benzodiazepines are used to treat anxiety;1075 17.7.8;Hallucinogens and Dissociative Drugs;1075 18.104.22.168;Hallucinogens produce an altered state of consciousness;1075 22.214.171.124;Phencyclidine (PCP) is a dissociative drug;1075 17.7.9;Addiction And Neuronal Plasticity Share Common Cellular Mechanisms;1076 126.96.36.199;Drugs of abuse rewire neuronal circuits by influencing synaptic plasticity;1076 188.8.131.52;Drugs of abuse have profound effects on transcription factors and gene expression;1076 184.108.40.206;Persistent adaptations may involve changes in the structure of dendrites and dendritic spines;1076 17.7.10;Acknowledgments;1077 17.7.11;References;1079 18;Glossary;1082 19;Index;1088
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