Basic Neurochemistry

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November 2011



Basic Neurochemistry: Principles of Molecular, Cellular, and Medical Neurobiology, the outstanding and comprehensive classic text on neurochemistry, is now newly updated and revised in its Eighth Edition. 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. It is also an excellent source of current information on basic biochemical and cellular processes in brain function and neurological diseases for continuing medical education and qualifying examinations. This text continues to be the standard reference and textbook for exploring the translational nature of neuroscience, bringing basic and clinical neuroscience together in one authoritative volume. Our book title reflects the expanded attention to these links between neurochemistry and neurologic disease. 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; Lipid messengers; Expanded coverage of all major neurodegenerative and psychiatric disorders; Neurochemistry of addiction; Neurochemistry of pain; Neurochemistry of hearing and balance; 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 chaptersOver 400 fully revised figures in splendid color61 chapters covering the range of cellular, molecular and medical neuroscienceTranslational science boxes emphasizing the connections between basic and clinical neuroscienceCompanion website at http://elsevierdirect.com/companions/9780123749475


1;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;Diverse cell types comprising the nervous system interact to create a functioning brain;29 10.1.3;Neurons: Common Elements and Diversity;29;The classic image of a neuron includes a perikaryon, multiple dendrites and an axon;29;Although neurons share common elements with other cells, each component has specialized features;31;The axon compartment comprises the axon hillock, initial segment, shaft and terminal arbor;34;Dendrites are the afferent components of neurons;34;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;Virtually nothing can enter or leave the central nervous system parenchyma without passing through an astrocytic interphase;36;Oligodendrocytes are myelin-producing cells in the central nervous system;38;The schwann cell is the myelin-producing cell of the peripheral nervous system;38 10.1.5;Microglia;40;The microglial cell plays a role in phagocytosis and inflammatory responses;40;Ependymal cells line the brain ventricles and the spinal cord central canal;41 10.1.6;BloodBrain Barriers and the Nervous System;41;Homeostasis of the central nervous system (CNS) is vital to the preservation of neuronal function;41;The BBB and BCSFB serve a number of key functions critical for brain function;42;Evolution of the bloodbrain barrier concept;43 10.1.7;The Neurovascul
ar Unit Includes Multiple Components;43;The lumen of the cerebral capillaries that penetrate and course through the brain tissue are enclosed by BECs interconnected by TJ;43;The basement membrane (BM)/basal lamina is a vital component of the BBB;44;Astrocytes contribute to the maintenance of the BBB;44;Pericytes at the BBB are more prevalent than in other capillary types;44;Brain endothelial cells restrict the transport of many substances while permitting essential molecules access to the brain;44;There are multiple transporters and transport processes for bidirectional transport at the BBB;46;Lipid solubility is a key factor in determining the permeability of a substance through the BBB by passive diffusion;46;The BBB expresses solute carriers to allow access to the brain of molecules essential for metabolism;47;Receptor-mediated transcytosis (RMT) is the primary route of transport for some essential peptides and signaling molecules;47;ATP-binding cassette transporters (ABC) on luminal membranes of the BBB restrict brain entry of many molecules;47;During development, immune-competent microglia develop and reside in the brain tissue;48;There is increasing evidence of BBB dysfunction, either as a cause or consequence, in the pathogenesis of many diseases affecting the CNS;48;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;Cells are bounded by proteins arrayed in lipid bilayers;51;Amphipathic molecules can form bilayered lamellar structures spontaneously if they have an appropriate geometry;52 10.2.2;Membrane Proteins;53;Membrane integral proteins have transmembrane domains that insert directly into lipid bilayers;53;Many t
ransmembrane proteins that mediate intracellular signaling form complexes with both intra- and extracellular proteins;54;Membrane associations can occur by selective protein binding to lipid head groups;54 10.2.3;Biological Membranes;54;The fluidity of lipid bilayers permits dynamic interactions among membrane proteins;54;The lipid compositions of plasma membranes, endoplasmic reticulum and golgi membranes are distinct;56;Cholesterol transport and regulation in the central nervous system is isolated from that of peripheral tissues;56;In adult brain most cholesterol synthesis occurs in astrocytes;56;The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling;57;The structure and roles of membrane microdomains (lipid rafts) in cell membranes are under intensive study but many aspects are still unresolved;58;Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton;59;The spectrinankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membrane;59;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;The reaction mechanism of Na,K-ATPase illustrates the mechanism of P-type pumps;67;Molecular structures of the catalytic subunits in the P-type transporters are similar;68;The active Na,K-ATPase is a heterodimer consisting of a catalytic a subunit and an accessory ß subunit;68;The a-subunit isoforms are expressed in a cell- and tissue-specific manner;68;The ß subunits are monotopic glycoproteins and exhibit some characteristics of cell adhesion molecules;68;The Na pump has associated . su
bunits;69;A major fraction of cerebral energy production is consumed by the Na,K pump;70;Na,K-ATPase Expression patterns change with development, aging and dementia;70;Na,K pump content in plasmalemma is regulated by its rapid endocyticexocytic cycling;70;The distributions of a-subunit isoforms provide clues to their different physiological functions;70;Regulatory factors direct the trafficking of Na,K-ATPase during its synthesis;71;The Na,K-ATPase/Src complex functions as a signal receptor for cardiotonic steroids (CTS);71;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;PMCA is a plasmalemma P-type pump with high affinity for Ca2+;73 10.3.6;Smooth Endoplasmic Reticulum Calcium Pumps (SERCA);73;SERCA, another P-type Ca pump, was first identified in sarcoplasmic reticulum;73;High-resolution structural data exist for the SERCA1a Ca pump;73 10.3.7;Other P-Type Transporters;75;P-type copper transporters are important for neural function;75 10.3.8;V0V1 Proton Pumps;75;The V0V1-ATPase pumps protons into golgi-derived organelles;75 10.3.9;ATP-Binding Cassettes;75;The ABC transporters are products of one of the largest known gene superfamilies;75;The Three-dimensional structures of several ABC transporters from prokaryotes have been determined;75;ABCA1 translocates cholesterol and phospholipids outward across the plasma membrane;76;The multidrug-resistance proteins (MDR) can flip amphipathic molecules;77 10.3.10;Secondary Active Transport;77;Brain capillary endothelial cells and some neurons express a Na-dependent D-glucose symporter;77;Neurotransmitter sodium symporters (NSS) effect the recovery of neurotransmitters from synaptic
clefts;77;There are two distinct subfamilies of neurotransmitter sodium symporters;77;The SLC6 subfamily of symporters for amino acid transmitters and biogenic amines is characterized by a number of shared structural features;77;SLC1 proteins encompass glutamate symporters as well as some amino- and carboxylic-acid transporters expressed in bacteria;78;The glutamate symporters in brain are coded by five different but closely related genes, SLC1A14 and SLC1A6;78;Failure of regulation of glutamate concentration in its synaptic, extracellular and cytosol compartments leads to critical pathology;79;Choline transporter: termination of the synaptic action of acetylcholine is unique among neurotransmitters;79;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;Na,Ca exchangers are important for rapidly lowering high pulses of cytoplasmic Ca2+;80;Na,K-ATPase a subunits are coordinated with Na,Ca antiporters and Ca pumps;80;The overall mechanism for regulation of cytosolic Ca2+ is complex;80 10.3.13;The Anion Antiporters;81;Anion antiporters comprising the SLC8 gene family all transport bicarbonate;81;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;Simple diffusion of polar water molecules through hydrophobic lipid bilayers is slow;81;Crystallographic and architectural data are available for AQP1 and AQP4;82;The aquaporins found in brain are AQP1, 4 and 9;82;In astrocytic perivascular endfeet membranes, AQP4 is anchored to the dystrophin complex of proteins;82;AQP4 exists in astrocyte membranes and is coordinated with other proteins with w
hich its function is integrated;82;Rapid diffusion of K+ and H2O from Neuronal extracellular space by astroglia is critical to brain function;83;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;Facilitated diffusion of glucose across the bloodbrain barrier is catalyzed by GLUT-1, -2 and -3;83;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;Excitable cells have a negative membrane potential;89;Real cells are not at equilibrium;90;Transport systems may also produce membrane potentials;90;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;During excitation, ion channels open and close and a few ions flow;91;Gating mechanisms for Na+ and K+ channels in the axolemma are voltage dependent;91;The action potential is propagated by local spread of depolarization;92;Membranes at nodes of ranvier have high concentrations of Na+ channels;92 10.4.3;Functional Properties of Voltage-Gated Ion Channels;92;Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane;92;Voltage-dependent gating requires voltage-dependent conformational changes in the protein component(s) of ion channels;93;Pharmacological agents acting on ion channels help define their functions;93 10.4.4;The Voltage-Gated Ion Channel Superfamily;94;Na+ channels were identified by neurotoxin labeling and their primary structures were established by cDNA cloning;94;Ca2+ channels have a structure similar to Na+ channels;96;Voltage-gated K+ channels wer
e identified by genetic means;96;Inwardly rectifying K+ channels were cloned by expression methods;96 10.4.5;The Molecular Basis for Ion Channel Function;96;Much is known about the structural determinants of the ion selectivity filter and pore;96;Voltage-dependent activation requires moving charges;99;The fast inactivation gate is on the inside;99 10.4.6;Ion Channel Diversity;100;Na+ channels are primarily a single family;100;Three subfamilies of Ca2+ channels serve distinct functions;100;There are many families of K+ channels;101;More ion channels are related to the NaV, CaV and KV families;101;There are many other kinds of ion channels with different structural backbones and topologies;102;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;Lipids have multiple functions in brain;107;Membrane lipids are amphipathic molecules;107;The hydrophobic components of many lipids consist of either isoprenoids or fatty acids and their derivatives;107;Isoprenoids have the unit structure of a five-carbon branched chain;107;Brain fatty acids are long-chain carboxylic acids that may contain one or more double bonds;107 10.5.3;Complex Lipids;108;Glycerolipids are derivatives of glycerol and fatty acids;108;In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone;110 10.5.4;Analysis of Brain Lipids;114;Chromatography and mass spectrometry are employed to analyze and classify brain lipids;114 10.5.5;Brain Lipid Biosynthesis;115;Acetyl coenzyme A is the precursor of both cholesterol and fatty acids;115;Phosphatidic acid is the precursor of all glycerolipids;119;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;Lipids are transported between membranes;123;Membrane lipids may be asymmetrically oriented;123;Some proteins are bound to membranes by covalently linked lipids;123;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;Along with the nucleus and mitochondria, the cytoskeleton is one of several biological structures that define eukaryotic cells;127;Microtubules act as both dynamic structural elements and tracks for organelle traffic;127;Neuronal and glial intermediate filaments provide support for neuronal and glial morphologies;131;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;A dynamic neuronal cytoskeleton provides for specialized functions in different regions of the neuron;135;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;Microfilament and microtubule dynamics underlie growth cone motility and function;137;The axonal cytoskeleton may be influenced by glia;137;Levels of cytoskeletal protein expression change after injury and during regeneration;139;Alterations in the cytoskeleton are frequent hallmarks of neuropathology;139;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;Most transport vesicles bud off as coated vesicles, with a unique set of proteins decorating their cytosolic surface;146;GTP-binding proteins, such as small monomeric GTPases and heterotrimeric GTPases (G proteins) facilitate membrane transport;147;Dynamins are involved in pinching off of many vesicles and membrane-bounded organelles;148;Removal of coat proteins is catalyzed by specific protein chaperones;149;SNARE proteins and rabs control recognition of specific target membranes;150;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;Historically, endoplasmic reticulum has been classified as rough or smooth, based on the presence (RER) or absence (SER) of membraneassociated polysomes;151;Biosynthetic and secretory cargo leaving the ER is packaged in COPII-coated vesicles for delivery to the Golgi complex;152;The Golgi apparatus is a highly polarized organelle consisting of a series of flattened cisternae, usually located near the nucleus and the centrosome;154;Processing of proteins in the Golgi complex includes sorting and glycosylation of membrane proteins and secretory proteins;154;Proteins and lipids move through Golgi cisternae from the cis to the trans direction;155;Plasma membrane proteins are sorted to their final destinations at the trans-Golgi network;156;Lysosomal proteins are also sorted and targeted in the trans-Golgi network;157;Several intracellular trafficking pathways converge at lysosomes;157;Both constitutive
and regulated neuroendocrine secretion pathways exist in cells of the nervous system;157;The constitutive secretory pathway is also known as the default pathway because it occurs in the absence of a triggering signal;159;Secretory cells, including neurons, possess a specialized regulated secretory pathway;159;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;Endocytosis for degradation of macromolecules and uptake of nutrients involves phagocytosis, pinocytosis and autophagy;160;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;The organization of the presynaptic terminal is one important element for optimization of secretion and recycling;164;In a simplistic model, the exocytosis step of neurotransmission takes place in at least three major different steps;164;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;The size and extent of many neurons presents a special set of challenges;172;Fast and slow components of axonal transport differ in both their constituents and their rates;173;Features of fast axonal transport demonstrated by biochemical and pharmacological approaches are apparent from video images;176 10.8.4;Fast Axonal Transport;176;Newly synthesized
membrane and secretory proteins destined for the axon travel by fast anterograde transport;176;Passage through the golgi apparatus is obligatory for most proteins destined for fast axonal transport;177;Anterograde fast axonal transport moves synaptic vesicles, axolemmal precursors, and mitochondria down the axon;178;Retrograde transport returns trophic factors, exogenous material, and old membrane constituents to the cell body;178;Molecular sorting mechanisms ensure delivery of proteins to discrete membrane compartments;179 10.8.5;Slow Axonal Transport;180;Cytoplasmic and cytoskeletal elements move coherently at slow transport rates;180;Axonal growth and regeneration are limited by rates of slow axonal transport;180;Properties of slow axonal transport suggest molecular mechanisms;181 10.8.6;Molecular Motors: Kinesin, Dynein and Myosin;181;The characteristic biochemical properties of different molecular motors aided in their identification;182;Kinesins mediate anterograde fast axonal transport in a variety of cell types;182;Mechanisms underlying attachment of motors to transported MBOs remain elusive;183;Multiple members of the kinesin superfamily are expressed in the nervous system;183;Cytoplasmic dyneins have multiple roles in the neuron;184;Different classes of myosin are important for neuronal function;185;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;Cell adhesion molecules comprise several superfamilies;191 10.9.2;Immunoglobulin Superfamily;191;The immunoglobulin (Ig)-like domain is a typical feature of proteins belonging to the immunoglobulin superfamily;191;Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) represent a divers
e group of proteins;191;IgCAMs signal to the cytoplasm;193 10.9.3;Cadherins;194;The extracellular cadherin (EC) repeat is a typical feature of cadherins;194;The type I (classic) cadherins are homophilic cell adhesion molecules;194;Cadherins are involved in multiple processes in the nervous system;194 10.9.4;Integrins;195;Integrins are the major cell surface receptors responsible for cell adhesion to extracellular matrix (ECM) proteins;195;Integrins signal in an inside-out and outside-in fashion;197;Integrins regulate myelination;198 10.9.5;Cooperation and Crosstalk between Cell Adhesion Molecules;200;Various cell adhesion molecules cooperatively regulate the formation of interneuronal synapses in the CNS;200;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;Myelin facilitates conduction;205;Myelin has a characteristic ultrastructure;206;Nodes of Ranvier;207;Myelin is an extension of a cell membrane;209;Myelin affects axonal structure;210 10.10.2;Characteristic Composition of Myelin;210;The composition of myelin is well characterized because it can be isolated in high yield and purity by subcellular fractionation;210;Central nervous system myelin is enriched in certain lipids;211;Peripheral and central nervous system myelin lipids are qualitatively similar;212;Central nervous system myelin contains some unique proteins;213;Proteolipid protein;213;Myelin basic proteins;214;2':3'-cyclic nucleotide 3'-phosphodiesterase;215;Myelin-associated glycoprotein (MAG) and other glycoproteins of CNS myelin;216;Peripheral myelin also contains unique proteins;217;P0 glycoprotein;217;Peripheral myelin pro
tein-22;217;P2 protein;218;Some classically defined myelin proteins are common to both CNS and PNS myelin;218;Myelin basic protein;218;Myelin-associated glycoprotein;218;Myelin sheaths contain other proteins, some of which have only recently been established as myelin related;219;Tetraspan proteins;219;Nodal, paranodal, and juxtaparanodal proteins;220;Enzymes associated with myelin;220;Neurotransmitter receptors associated with myelin;222;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;Processes related to signaling require a larger proportion of energy than do basic cellular functions;226;Function-derived signals arising from metabolism are used for brain imaging;227;Major cell types and their subcellular structures have different energetic requirements and metabolic capabilities;228 10.11.2;Substrates for Cerebral Energy Metabolism;228;Energy-yielding substrates enter the brain from the blood through the bloodbrain barrier;228;Endothelial cells of the bloodbrain barrier and brain cells have specific transporters for the uptake of glucose and monocarboxylic acids;228;Bloodbrain barrier transport can be altered under pathological conditions;229 10.11.3;Age and Development Influence Cerebral Energy Metabolism;229;The transporters and pathways of metabolism change during development;229;Cerebral metabolic rate increases during early development;230;Cerebral metabolic rate declines from developmental levels and plateaus after maturation;230 10.11.4;Fueling Brain: SupplyDemand Relationships and Cerebral Metabolic Rate;230;Both excitatory and inhibitory neuronal signals utilize energy derived from metabolism;230;Continuous cerebral circulation
is required to sustain brain function;231;Glucose is the main obligatory substrate for energy metabolism in adult brain;231 10.11.5;Metabolism in the Brain is Highly Compartmentalized;232;Glucose has numerous metabolic fates in brain;232 10.11.6;Glycolysis: Conversion of Glucose to Pyruvate;232;Regulation of brain hexokinase;232;Phosphofructokinase is the major regulator of brain glycolysis;233;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;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;The malateaspartate shuttle is the most important pathway for transferring reducing equivalents from the cytosol to the;235;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;Lactatepyruvate interconversion;236;Lactate is formed in brain under many conditions;236;Compartmentation of the pyruvatelactate pool is unexpectedly complex;239;Lactate can serve as fuel for brain cells under various conditions;239;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;The TCA (citric acid) cycle is multifunctional;240;The pyruvate dehydrogenase complex plays a key role in regulating oxidation of glucose;242;TCA cycle rate;242;Malate dehydrogenase is one of several enzymes in the TCA cycle present in both the cytoplasm an
d mitochondria;242;The electron transport chain produces ATP;242;ATP production in brain is highly regulated;242;Phosphocreatine has a role in maintaining ATP levels in brain;243;Pyruvate carboxylation in astrocytes is the major anaplerotic pathway in brain;243;Citrate is a multifunctional compound predominantly synthesized and released by astrocytes;243;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;Mitochondria are distributed with varying densities throughout the central nervous system, with the more vascular parts;244;Mitochondrial heterogeneity leads to multiple simultaneous TCA cycles in astrocytes and neurons;244;Partial TCA cycles can provide energy in brain;244;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;Transporters are required to carry glutamate and other amino acids across the mitochondrial membrane;245;Metabolism of both glutamate and glutamine is linked to TCA cycle activity;245;Glutamate participates in a number of metabolic pathways, and metabolism of glutamate and glutamine is compartmentalized;245;The glutamateglutamine cycle;246;A specialized glutamateglutamine cycle operates in Gabaergic neurons and surrounding astrocytes;247;Several shuttles act to transfer nitrogen in brain;247 10.11.14;Metabolic Studies in Brain: Imaging and Spectroscopy;247;Global assays of whole brain;247;Local rates of glucose and oxygen utilization, functional brain imaging, redox state, and metabolic pathway analysis;247;Carbon-13 nuc
lear magnetic resonance spectroscopy (NMR or MRS) for studying brain metabolism;249;Cultured neurons and astrocytes are useful for studying subcellular compartmentation and identifying pathways of metabolism;250;Metabolic assays in brain slices, axons, synaptosomes and isolated mitochondria;251;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;Chemical transmission between nerve cells involves multiple steps;260;Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells;262;A variety of methods have been developed to study exocytosis;263;The neuromuscular junction is a well-defined structure that mediates the release and postsynaptic effects of acetylcholine;263;Quantal analysis defines the mechanism of release as exocytosis;264;Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis;264;Presynaptic events during synaptic transmission are rapid, dynamic and interconnected;266;Because fast synaptic transmission involves recycling vesicles, the neurotransmitter must be replenished locally;270;Discrete steps in the regulated secretory pathway can be defined in neuroendocrine cells;270 11.1.2;Cellular Signaling Mechanisms;270;Background;270;Three phases of receptor-mediated signaling can be identified;271;Several major molecular mechanisms that link agonist occupancy of cell-surface receptors to functional responses have been identified;271;First group;271;Second group;2
73;Third group;273;Fourth group;273;Cross-talk can occur between intracellular signaling pathways;274;Signaling molecules can activate gene transcription;274;Nitric oxide acts as an intercellular signaling molecule in the central nervous system;274;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;Acetylcholine formation is catalyzed by choline acetyltransferase;285;Choline is accumulated into synaptic terminals via a specific high-affinity transporter;285;ACh is packaged into vesicles by a specific transporter and is released from neurons in a Ca2+-dependent manner;286;Cholinergic neurons are widely distributed within the CNS;287 11.2.3;Enzymatic Breakdown of Acetylcholine;287;Acetylcholinesterase and the removal of ACh;287;Molecular forms of AChE;287;AChE is encoded by a single gene that is subject to alternative splicing;288;AChE catalysis: mechanism of a nearly perfect enzyme;288;The active site is at the bottom of a narrow gorge in the AChE protein;289;Inhibitors of AChE have toxicological, agrochemical and clinical significance;290;Does AChE have other functions?;291 11.2.4;Nicotinic Cholinergic Receptors;291;The nicotinic receptor was the first receptor to be characterized biochemically;291;nAChRs are pentameric ligand-gated ion channels;292;Agonists bind at the interface between adjacent subunits;293;The nAChR is the prototypical member of the cys-loop family of ligand-gated ion channel receptors;294;The nAChR ion channel;294;The prolonged presence of agonist leads to desensitization;294;Neuronal nAChRs form a family of rela
ted receptors;294;The permutations of subunits forming nAChRs create more diversity;296;Neuronal nAChRs modulate brain function;296;Transgenic mice help to reveal the physiological roles and clinical implications of nAChRs;296;Neuronal nAChRs are also present in non-neuronal cells;297;nAChRs and disease;297;nAChRs as therapeutic targets;298 11.2.5;Muscarinic Cholinergic Receptors;299;Some effects of ACh can be mimicked by the alkaloid muscarine;299;Muscarinic cholinergic responses are mediated by G-proteincoupled receptors;299;Pharmacological studies were the first to indicate the presence of multiple mAChR subtypes;299;Molecular cloning of the mAChR reveals five subtypes;300;Muscarinic receptor subtypes couple to distinct G-proteins and activate different effector mechanisms;301;Muscarinic receptor subtypes are not uniformly distributed throughout the CNS and are present at different subcellular locations;302;Muscarinic receptors in the CNS have been implicated in a number of neuropsychiatric disorders;302;Transgenic mice permit an assessment of the physiological roles of individual subtypes in vivo;302;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;Catecholamines belong to the group of transmitters called monoamines;308;Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis;309;Aromatic amino acid decarboxylase (AAAD), also called DOPA decarboxylase, catalyzes the conversion of L-DOPA to dopamine;310;In noradrenergic and adrenergic neurons, dopamine is further converted to norepinephrine by Dopamine-ß-hydroxylase (DBH);311;In select neurons and adrenal medulla, norepinephrine is metabolized to epinephrine by phenylethanolamine-n-methyltransferase (PNM
T);313;Catecholamines are stored in small, clear synaptic vesicles or large, dense-core granules;313;Catecholamines are released from synaptic vesicles and the vesicles recycle;313;The physiological actions of catecholamines are terminated by reuptake into the neuron, catabolism and diffusion;313;Diffusion also plays an important role in the inactivation of catecholamines;315;Catecholamines are primarily metabolized by monoamine oxidase and catechol-o-methyltransferase;315;Monoamine oxidase (MAO);315;Catechol-O-methyltransferase (COMT);316;Dopamine metabolites;317;Norepinephrine metabolism;317 11.3.2;Neuroanatomy;317;Catecholamines elicit their effects by binding to cell-surface receptors;318 11.3.3;Adrenergic Receptors;320;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;The indolealkylamine 5-hydroxytryptamine (5-HT; serotonin) was initially identified because of its effects on smooth muscle;326;Understanding the neuroanatomical organization of serotonergic neurons provides insight into the functions of this neurotransmitter;326;The amino acid L-tryptophan serves as the precursor for the synthesis of 5-HT;329;The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter;331;As with other biogenic amine transmitters, 5-HT is stored primarily in vesicles and is released by an exocytotic mechanism;331;The activity of 5-HT in the synapse is terminated primarily by its reuptake into serotonergic terminals;333;Acute and chronic regulation of SERT function provides mechanisms for altering synaptic 5-HT concentrations and neurotransmission;334;The primary catabolic pathway for 5-HT is oxidative deaminat
ion by the enzyme monoamine oxidase;335;In addition to classical synaptic transmission, 5-HT may relay information by volume transmission or paracrine neurotransmission;336;5-HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state;336;5-HT modulates neuroendocrine function;337;5-HT modulates circadian rhythmicity;337;5-HT modulates feeding behavior and food intake;337 11.4.2;Serotonin Receptors;338;Pharmacological and physiological studies have contributed to the definition of the many receptor subtypes for serotonin;338;The application of techniques used in molecular biology to the study of 5-HT receptors led to the rapid discovery of addition;339;The 5-HT1 receptor family is composed of the 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-HT1F receptors;339;The 5-HT1A receptor;339;The 5-HT1B and 5-HT1D receptor subtypes;341;The 5-ht1E receptor;342;The 5-HT1F receptor;342;The 5-HT2 receptor family is composed of the 5-HT2A, 5-HT2B and 5HT2C receptors;342;5-HT2A receptors;342;The 5-HT2B receptor;343;The 5-HT2C receptor;343;Unlike the other subtypes of receptor for 5-HT, the 5-HT3 receptor is a ligand-gated ion channel;343;The 5-HT3 receptor;343;The 5-HT4, 5-HT6 and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase;344;The 5-HT4 receptor;344;The 5-HT6 receptor;345;The 5-HT7 receptor;345;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;Histamine is a mediator of several physiological and pathological processes within and outside of the nervous system;349;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;The brain stores and releases histamine from more than one type of cell;349;Several functions for brain and dural mast cells are investigated;349;Histaminergic fibers originate from the tuberomamillary (TM) region of the posterior hypothalamus;349;Histaminergic neurons have morphological and membrane properties that are similar to those of neurons storing other biogenic amines;350;Histaminergic fibers project widely to most regions of the central nervous system;350 11.5.4;Dynamics of Histamine in the Brain;352;Specific enzymes control histamine synthesis and breakdown;352;Several forms of histidine decarboxylase (HDC) may derive from a single gene;353;Histamine synthesis in the brain is controlled by the availability of l-histidine and the activity of HDC;353;Histamine is stored within and released from neurons;353;In the vertebrate brain, histamine metabolism occurs predominantly by methylation;353;Neuronal histamine can be methylated outside of histaminergic nerve terminals;353;A polymorphism in human HMT (Thr105Ile) may be an important regulatory factor in some human disorders;354;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;Histamine acts on four G-proteincoupled receptors (GPCRs), three of which are clearly important in the brain;354;H1 receptors are intronless GPCRs linked to Gq and calcium mobilization;354;H1-linked intracellular messengers;355;H2 receptors are intronless GPCRs linked to Gs and cyclic AMP synthesis;356;H2-linked intracellular messengers;356;H3 receptors are a family of GPCRs produced by gene splicing and l
inked to Gi/o;356;H3 receptor gene splicing;358;H3-linked intracellular messengers;358;Constitutive H3 receptor activity;359;H4 receptors are very similar to H3 receptors in gene structure and signal transduction, but show limited expression in the brain;359;H4-linked intracellular messengers;360;Histamine can modify ionotropic transmission;360 11.5.6;Histamine Actions on the Nervous System;360;Histamine in the brain may act as both a neuromodulator and a classical transmitter;360;Histaminergic neurons are mutually connected with other neurotransmitter systems;360;Histamine functions in the nervous system;361;Histamine may contribute to nervous system diseases or disorders;362 11.5.7;Significance of Brain Histamine for Drug Action;362;Many clinically available drugs that modify sleepwake cycles and appetite act through the histaminergic system;362;Drugs that modify pain perception act in part through the histaminergic system;362;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;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;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;Seven functional families of ionotropic glutamate receptor subunits can be defined by structural homologies;373;AMPA and kainate receptors are both blocked by quinoxalinediones but have different desensitization pharmacologies;375;N-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites;375;The transmembrane topology of glutamate receptors differs from that of nicotinic receptors;379;Structure of the agonist-binding site has been analyzed;379;Genetic regulation via splice variants and RNA editing further increases receptor heterogeneity: the flip/flop versions;379;The permeation pathways of all ionotropic glutamate receptors are similar, but vive la difference;381 11.6.10;Glutamate Produces Excitatory Postsynaptic Potentials;381;Genetic knockouts provide clues to ionotropic receptor functions;383 11.6.11;Metabotropic Glutamate Receptors Modulate Synaptic Transmission;383;Eight metabotropic glutamate receptors (mGlu receptors) have been identified that embody three functional classes;383;mGlu receptors are linked to diverse cytoplasmic signaling enzymes;383;Postsynaptic mGlu receptor activation modulates ion channel activity;383;Presynaptic mGlu receptor activation can lead to presynaptic inhibition;384;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;A major scaffolding protein of the PSD is PSD95;385;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;Glutamate and its analogs can be neurotoxins and cause excitotoxicity;388;Some dietary neurotoxins may cause excessive glutamate receptor activation and cell death;388;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;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;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;GABAB receptors are coupled to G proteins and a variety of effectors;394;GABAB receptors are heterodimers;394;GABAA receptors are chloride channels and members of a superfamily of ligand-gated ion channel receptors;395;A family of pentameric GABAA-receptor protein subtypes exists; these vary in their localization, and in virtually every pro ...;395;The GABAA receptor is the major molecular target for the action of many drugs in the brain;397;Neurosteroids, which may be physiological endogenous modulators of brain activity, enhance GABAA receptor function;399;The three-dimensional structures of ligand-gated ion channel receptors are being modeled successfully;399;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;Extracellular nucleotides are regulated by ectoenzymes;404;There are several sources of extracellular adenosine;404 11.8.3;Purinergic Receptors;407;There are four adenosine receptor subtypes;407;Adenosine A1 receptors (A1R);408;A2A adenosine receptors are highly expressed in the basal ganglia;408;A2B adenosine receptors regulate vascular permeability;409;A3 adenosine receptors are few in number in the central nervous system;409;P2 receptors are subdivided into ionotropic P2X receptors and metabotropic P2Y receptors;409 11.8.4;Effects of Purines in the Nervous System;409;ATP-adenosine is an important glial signal;409;Myelination and importance of the axonal release of ATP;410;Astrocyte-mediated, adenosine-dependent heterosynaptic depression;410;Behavioral roles for glial-derived ATP and adenosine: respiration and sleep;410;pH-dependent release of purines from astrocytes controls breathing;411;Microglia and their response to injury;411;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;Many neuropeptides were originally identified as pituitary or gastrointestinal hormones;415;Peptides can be grouped by structural and functional similarity;416;The function of peptides as first messengers is evolutionarily very old;417;Vari
ous techniques are used to identify additional neuropeptides;417;The neuropeptides exhibit a few key differences from the classical neurotransmitters;417;Neuropeptides are often found in neurons with conventional neurotransmitters;418;The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters;419;Many of the enzymes involved in peptide biogenesis have been identified;419;Neuropeptides are packaged into large, dense-core vesicles;424;Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modification;424 11.9.2;Neuropeptide Receptors;425;Most neuropeptide receptors are seven-transmembrane-domain, G-proteincoupled receptors;425;Neuropeptide receptors are not confined to synaptic regions;426;Expressions of peptide receptors and the corresponding peptides are not well matched;427;The amiloride-sensitive FMRF-amide-gated sodium ion channel is among the few peptide-gated ion channels identified;427;Neuropeptide receptors are becoming molecular targets for therapeutic drugs;427 11.9.3;Neuropeptide Functions and Regulation;427;The study of peptidergic neurons requires a number of special tools;427;Peptides play a role in the plurichemical coding of neuronal signals;428;Neuropeptides make a unique contribution to signaling;428;Regulation of neuropeptide expression is exerted at several levels;428 11.9.4;Peptidergic Systems in Disease;429;Diabetes insipidus occurs with a loss of vasopressin production in the Brattleboro rat model;429;Mutations and knockouts of peptide-processing enzyme genes cause a myriad of physiological problems;429;Neuropeptides play key roles in appetite regulation and obesity;430;Enkephalin knockout mice reach adulthood and are healthy;430;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;The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions;436;Multiple forms of heterotrimeric G protein exist in the nervous system;437;Each G protein is a heterotrimer composed of single a, ß and . subunits;437;The functional activity of G proteins involves their dissociation and reassociation in response to extracellular signals;437;G proteins couple some neurotransmitter receptors directly to ion channels;437;G proteins regulate intracellular concentrations of second messengers;439;G proteins have been implicated in membrane trafficking;440;G protein ß. subunits subserve numerous functions in the cell;440;The functioning of heterotrimeric G proteins is modulated by other proteins;441;G proteins are modified covalently by the addition of long-chain fatty acids;443;The functioning of G proteins may be influenced by phosphorylation;443 12.1.2;Small G Proteins;443;The best-characterized small G protein is the Ras family, a series of related proteins of 21 kDa;443;Rab is a family of small G proteins involved in membrane vesicle trafficking;444 12.1.3;Other Features of G Proteins;444;G proteins can be modified by ADP-ribosylation catalyzed by certain bacterial toxins;444;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;Biochemistry of cAMP production;448;Adenylyl cyclase isozymes: expression and regulation;450;Group 1 adenylyl cyclases;450;Adenylyl Cyclase 1;450;Adenylyl Cyclases 3 and 8;451
;Group 2 adenylyl cyclases;451;Adenylyl Cyclase 2;451;Adenylyl Cyclase 4 and 7;451;Group 3 adenylyl cyclases;452;Adenylyl Cyclase 5;452;Adenylyl Cyclase 6;452;Group 4 adenylyl cyclase;452;Soluble adenylyl cyclase;452;Models for cellular regulation of the different types of adenylyl cyclase;452;Long-term regulation of adenylyl cyclases;454;Molecular targets of cAMP;454;Protein kinase A;454;Cyclic nucleotide-gated channels;454;Epac;455;Functions of cAMP signaling in the brain;455;Synaptic plasticity, learning, and memory;455;Pain;455;Dopamine signaling in the striatum;455;Neurodegeneration;455;Drugs of abuse;455;Olfaction;455 12.2.3;Guanylyl Cyclases;455;Membrane-bound guanylyl cyclase;456;GC-A, -B and -C are receptors for natriuretic peptides;457;GC-D and GC-G are implicated in olfaction;457;GC-E and GC-F are involved in photoreceptor signal transduction;457;Soluble guanylyl cyclases;457;sGC is regulated by nitric oxide (NO);458;Molecular effectors of cGMP signaling;458;Protein kinase G;458;cGMP-gated ion channels;458;Phosphodiesterases;458;Functions of cGMP signaling in the brain;458;Synaptic plasticity, learning, and memory;459;Cognition and mood;459;Pain;459 12.2.4;Phosphodiesterases;459;Structure of phosphodiesterases;459;Families of phosphodiesterases;459;Ca2+/calmodulin-stimulated PDEs (PDE1);459;cGMP-regulated PDEs (PDE2, PDE3, and PDE11);460;G proteinactivated phosphodiesterase in retinal phototransduction: PDE6;461;PDEs regulated primarily by phosphorylation: PDE4, 5 and 10;462;PDE7, 8 and 9;463;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;The three quantitatively major phosphoinositides are structurally and metabolically related;468;The quantitatively minor 3'-phosphoinositides are synthesized by phosphatidylinositol 3-kinase;469;Phosphoinositides are dephosphorylated by phosphatases;470;Phosphoinositides are cleaved by a family of phosphoinositide-specific phospholipase C (PLC) isozymes;471 12.3.3;The Inositol Phosphates;473;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;The metabolism of inositol phosphates leads to regeneration of free inositol;474;Highly phosphorylated forms of myo-inositol are present in cells;474 12.3.4;Diacylglycerol;474;Protein kinase C is activated by the second messenger diacylglycerol;474 12.3.5;Phosphoinositides and Cell Regulation;476;Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers;476;Membrane trafficking;476;Cell growth and cell survival;477;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;Much of our understanding of the essential role of Ca2+ in cellular physiology has been indirect;481;Current optical methods to measure calcium use chemical or protein-based fluorescent indicators;481;The optical monitoring of [Ca2+] relies on indicators whose fluorescence changes upon binding to calcium;481;Increased resolution can be accomplished optically or by targeting indicator proteins;482 12.4
.3;Calcium Homeostasis at the Plasma Membrane;482;The balance between calcium efflux and influx at the plasma membrane determines [Ca2+];482;Efflux pathways pumps and transporters;483;Influx pathways Ca enters the cell through four major routes;483 12.4.4;Cellular Organelles and Calcium Pools;483;The endoplasmic reticulum is the primary intracellular calcium store;484;The ER has pumps, storage buffersand Ca2+ release channels;484;Activation of different ER signaling pathways elicit different responses;484;Store-operated Ca2+ entry: The ER signals when empty to open channels in the plasma membrane;485;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;Electrically silent astrocytes use Ca2+ as a signaling molecule;486;The tripartite synapse: gliotransmitters and modulation of transmission at the synapse;487;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;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;Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation;495;Second messengerdependent protein Ser/Thr kinases;498;cAMP-dependent protein kinase;498;cGMP-dependent protein kinase;498;Protein kinase C;498;Calcium2+/calmodulin-dependent kinases;500;Second messengerindependent protein Ser/Thr kinases;501;The MAPK cascade is a classical example of second messengerindependent protein Ser/Thr kinase signaling;5
01;Extracellular signal-regulated protein kinases (ERKs);502;p38 MAPKs;502;c-Jun NH2-terminal kinases;502;The brain contains many other types of second messengerindependent protein Ser/Thr kinases;503;Cyclin-dependent kinase 5 (CDK5);503;Glycogen-synthase kinase-3 (GSK3);503;Casein kinase 1 (CK1);503;Protein phosphatase 1 (PP1);504;Protein phosphatase 2A (PP2A);505;Protein phosphatase 2B (PP2B);505;Protein phosphatase 2C (PP2C);506;Dual-specificity phosphatases (DUSPs);506 12.5.3;Protein Ser/Thr Phosphatases;504;Common strategies used for the evaluation of neuronal functions of protein kinases and phosphatases;506 12.5.4;Neuronal Phosphoproteins;507;Phosphorylation can influence protein function in various ways;507;Proteins are often subject to complex phosphoregulation;508;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;Presynaptic mechanisms regulated by protein phosphorylation;510;Postsynaptic mechanisms regulated by protein phosphorylation;512;Extrasynaptic mechanisms regulated by protein phosphorylation;514 12.5.6;Protein Phosphorylation in Human Neuronal Disorders;514;Genetic neuronal disorders due to mutations in genes of protein kinases and phosphatases;514;Protein phosphorylation in pathophysiological processes in diseases of the nervous system;515;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;Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper;519;Receptor protein tyrosine kinases consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domain;523;RPTK Activation;525;RPTK Inactivation;525;Tyrosine Phosphorylation of RPTKs;526 12.6.3;Protein Tyrosine Phosphatases;526;Protein tyrosine phosphatases are structurally different from serinethreonine phosphatases and contain a cysteine residue;528;Nonreceptor tyrosine phosphatases are cytoplasmic and have regulatory sequences flanking the catalytic domain;529;Receptor protein tyrosine phosphatases consist of an extracellular domain, a transmembrane domain and one or two intracellular;530;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;Tyrosine phosphorylation is involved in every stage of neuronal development;530;Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse;534;Tyrosine phosphorylation contributes to the formation of synapses in the central nervous system;534;Acetylcholine Receptors;535;N-Methyl-d-Aspartate Receptors;535;GABA Receptors;536;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;Co-regulators of transcriptionmodulation of chromatin structure;541;Histone acetylation;541;Histone and DNA methylation;542 12.7.2;Regulation of Transcription by Transcription Factors;543;Technology that has hastened the study of transcription;543;NextGen sequencing to assess the cellular transcriptome;545 12.7.3;Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors;546;Corticosteroid receptors regulate transcription in the nervous system;547;The mechanisms of
corticosteroid receptor regulation of transcription have been elucidated;547 12.7.4;camp Regulation of Transcription;549;The cAMP response elementbinding protein is a member of a family containing interacting proteins;550;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;Transcription factors navigate the roadmap of cellular maturation;552;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;The CNS arises from the neural tube;559;The major divisions of the CNS are identifiable early in development;559 13.1.3;Spatial Regionalization;559;A dorsoventral pattern arises with signals from adjacent non-neuronal cells;559;The rostrocaudal axis is specified by homeobox-containing genes;560;Embryonic signaling centers organize large regions of the brain;563 13.1.4;Neurogenesis and Gliogenesis;564;Neurons have a birthdate;564;Reelin and notch signaling contribute to cortical layer organization;564;Neuronal specification involves proneural and neurogenic gene gunctions;565 13.1.5;PNS Development and Target Interactions;566;The neural crest gives rise to PNS derivatives by induction;566 13.1.6;Axon Guidance Contributes to Correct Connections;567;Naturally occurring cell death eliminates cells and synapses;567 13.1.7;Synapse Formation;568;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;Nerve growth factor;572;Brain-derived neurotrophic factor;573;Neurotrophin 3;575;Neurotrophin 4;575 13.2.3;Regulation of Neurotrophin Expression;576 13.2.4;Proneurotrophins;576 13.2.5;Neurotrophin Receptors;576;Trk receptors;577;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;Embryonic stem (ES) cells are derived from the inner cell mass of embryos;584;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;Neural stem cells (NSCs);585;Radial glia are stem cells;585;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;Stem cell markers in the nervous system;586;The neurosphere functional assay;586;Is there a brain neoplasm stem cell?;587;Induced pluripotent stem cells, reprogramming and directed differentiation;587 13.3.5;Stem Cells Offer Potential for Repair in the Adult Nervous System;588;Stem cells to replace depleted neurochemicals: Parkinsons disease;588;Stem cell treatment to deliver missing enzymes or proteins: leukodystrophies;589;Stem cells for cell replacement therapy: myelin;589;Stem cells as a source of growth factors and guidance cues;590;Stem cells for immunomodulation: multiple sclerosis;591;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;Myelination occurs during nervous system development and is essential for normal nervous system function;595 13.4.2;Schwann Cell Development;595;Schwann cells are the myelinating cells of the peripheral nervous system;595;Schwann cell lineage differentiation is regulated by a series of transcription factors;595 13.4.3;Oligodendrocyte Development;595;Oligodendrocytes are the myelinating cells of the CNS;595;Much early work was possible because of in vitro analysis of the oligodendrocyte cell lineage;595;The discovery of several transcription factors that are expressed at early stages of oligodendrocyte specification and;596;A number of transcriptional and epigenetic regulators control oligodendrocyte progenitor cell differentiation into;597 13.4.4;Regulation of Myelination;599;Extensive recent research has focused on identifying the axonal signals that regulate myelination;599 13.4.5;Developmental and Metabolic Aspects of Myelin;600;Synthesis of myelin components is very rapid during deposition of myelin;600;Sorting and transport of lipids and proteins takes place during myelin assembly;600;The composition of myelin changes during development;601 13.4.6;Genetic Disorders of Myelination;601;Rodent mutants of myelination have been investigated since the 1950s;601 13.4.7;Myelin Maintenance;602;Maintenance of myelin once it is formed is a poorly understood process;602;Myelin components exhibit great heterogeneity of metabolic turnover;602;There are signal transduction systems in myelin sheaths;602;The dynamic nature of myelin sheaths likely contributes to the functional state of axons;603;Peripheral neuropathies result from loss of myelin in the peripheral nervous system;603 1;A number of environmental toxins impact myelination during development or myelin maintenance in the adult;603;Leukodystrophies define a number of genetic disorders that impact CNS myelination (dysmyelination) or myelin maintenance once;603 13.4.8;Remyelination;604;Peripheral nerve regeneration has been studied extensively;604;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;Wallerian degeneration is the secondary disruption of the myelin sheath and axon distal to the injury;608;The molecular and cellular events during Wallerian degeneration in the PNS transform the damaged nerve into an environment;608;Both Schwann cells and basal lamina are required for axonal regeneration to proceed;609;Cell surface adhesion molecules, which promote regeneration, are expressed on plasmalemma of both Schwann cells and regenerating;610;Structural and biochemical changes occur after axotomy;610 13.5.3;Regeneration in the Central Nervous System;610;Central nervous system myelin contains molecules that inhibit neurite growth;610;Nogo-A is a potent inhibitor of neurite growth and blocks axonal regeneration in the central nervous system;611;Nogo gene is a member of the reticulon superfamily;612;Nogo-A function-blocking antibodies and peptides lead to axonal growth and functional recovery in vivo;613;Lines of knockout mice null for the Nogo genes have been developed;613;Additional myelin components have growth-inhibitory activity;613;Inhibition of neurite growth is mediated through surface receptors and intracellular signaling molecules;6
14;Neuronal expression of Nogo-A regulates neurite outgrowth;614;Axon growth is inhibited by the glial scar;614;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;Neonatal brain damage results in compensatory plasticity;615;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;Definition: What is neuroimmunology?;622;Scope: Are neuroimmune interactions relevant only in the context of immune-mediated neurodegenerative disorders?;623;Relevance: A real-world example;623 14.1.2;Distinguishing Friend from FOE;624;Innate versus adaptive immunity: two interacting types of immune recognition;624;Innate immunity is triggered by evolutionarily conserved alarm signals;624;Adaptive immunity can recognize evolutionarily novel molecules;624;Antigen presentation by major histocompatibility-complexexpressing cells is required to activate T-cells;624;Antigen-activated T-cells regulate the activation of innate immune cells;626;The activation state of the antigen-presenting cell regulates T cell activation and phenotype;626;Choosing between immune tolerance and inflammation;626;Antigen presentation in the absence of alarm signals promotes tolerance;627;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;Functional consequences of lymphoid tissue innervation;627;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;The BBB and CNS-specific regulation of leukocyte influx and efflux;629;Leukocyte migration into the CNS parenchyma is a two-step process;629;Microglia, a CNS-specific macrophage and antigen-presenting cell;630;Distinguishing CNS-resident microglia from CNS-infiltrating macrophages;630;Microglia are not effective at initiating antigen-driven T-cell functions;631;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;The role of microglia in neuroinflammation;636 14.2.2;The Highly Regulated Activation of Microglia and Phagocytosis;637;Microglial activation;637;Microglial phagocytosis;637;Receptors in microglia;637;Microglia in neurodegenerative diseases;638 14.2.3;Microglial Dysfunction During Aging;638 14.2.4;Protein Aggregation;638;The effects of protein aggregation on microglial function;639 14.2.5;Cytokines/Chemokines;639;Cytokines are responsible for microglia activation;639;Cytokines are produced by activated microglia;639;Anti-inflammatory interleukin-10 and TGF-ß1;639 14.2.6;Lipid Mediator Pathways in Neuroinflammation;639;Initiation of inflammation: prostaglandin and leukotriene pathways;639;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;Aß Immunotherapy;641;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;Focal cerebral ischemia;647;Global cerebral ischemia;648 14.3.2;Injury in the Ischemic Phase;652;Excitotoxic glutamate neurotransmitter;652;Excitotoxicity;652;Ca2+ overloading in the ischemic injury;652;NMDA receptors, brain function and cell death;653;Downstream cell death signals of NMDA receptors;654 14.3.3;Brain Injury During the Reperfusion Phase: Free Radicals in IschemiaReperfusion Injury;654;Reactive oxygen species contribute to the injury;654;Mitochondria, nitric oxide synthase and polyunsaturated fatty acid metabolism are sources of reactive oxygen species during;655;Polyunsaturated fatty acids generate reactive oxygen species;655;Brain antioxidants contribute to the protection of brain from ischemiareperfusion injury;655;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;Metalloproteinases during the neurovascular unit disruption;656;Significance of aquaporins in brain edema;657 14.3.5;Neuroprotection Signaling and Resolution of Inflammation: Mechanisms;657;Inflammatory mediators and anti-inflammatory regulation;657;Apoptotic signaling;658;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;Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli
;669;Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli;670;Phospholipids in synaptic membranes are an important target in seizures, traumatic brain injury, neurodegenerative diseases;670;Some molecular species of phospholipids in excitable membranes are reservoirs of bioactive lipid mediators that act as;670;Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second;670 14.4.2;Phospholipases A2;672;Phospholipases A2 catalyze the cleavage of the fatty acyl chain from the sn-2 carbon of the glycerol backbone of phospholipids;672;Cytosolic phospholipases A2 are involved in bioactive lipid formation;672;Ischemia and seizures activate phospholipases A2, releasing arachidonic and docosahexaenoic acids;672;Secretory phospholipases A2 are of relatively low molecular weight and have a high number of disulfide bridges, making them;672;There are high-affinity receptors that bind secretory phospholipases A2;672 14.4.3;Eicosanoids;673;Arachidonic acid is converted to biologically active derivatives by cyclooxygenases and lipoxygenases;673;Prostaglandins are very rapidly released from neurons and glial cells;673;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;Platelet-activating factor is a very potent and short-lived lipid messenger;675;Ischemia and seizures increase platelet-activating factor content in the brain;677 14.4.5;Cyclooxygenases;677;The cyclooxygenases are heme-containing enzymes that convert arachidonic acid to prostaglandin H2;677;Platelet-activating factor is a transcriptional activator of cyclooxygenase-2;677;COX-derived AA metabolites play multiple important roles i
n CNS;677;Cyclooxygenase-2 participates in aberrant synaptic plasticity during epileptogenesis;677 14.4.6;Lipoxygenases;678;The lipoxygenases are involved in the rate-determining step in the biosynthesis of leukotrienes, lipoxins, resolvins, and protectins;678;5-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 5-position to form 5-HpETE;678;15-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 15-position to Form 15-HpETE;678;LOs and LO-derived products play important roles in a variety of inflammatory disorders;679 14.4.7;Diacylglycerol Kinases;679;The slow glutamate responses are mediated through metabotropic receptors coupled to G proteins;679 14.4.8;Lipid Signaling in Neuroinflammation;679;A platelet-activating-factor-stimulated signal-transduction pathway is a major component of the kainic-acid-induced;679;In cerebrovascular diseases, the phospholipase-A2-related signaling triggered by ischemiareperfusion may be part of a delicate;679;Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, are products of membrane lipid breakdown;679;Free fatty acid release during cerebral ischemia is a complex process that includes the activation of signaling cascades;680;The rate of free fatty acid production in the mammalian brain correlates with the extent of resistance to ischemia;681;Activation of the arachidonic acid cascade during ischemiareperfusion is a multistage process;681;Cyclooxygenase and lipoxygenase products accumulate during reperfusion following cerebral ischemia;681;The cerebrovasculature is also an abundant source of eicosanoids;681 14.4.9;Docosahexaenoic Acid;681;Brain and retina are the tissues containing the highest contents of docosahexaenoic acid;681;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;Docosahexaenoic-acidcontaining phospholipids are targets for lipid peroxidation;682 14.4.11;Docosanoids;682;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;Docosanoids, enzyme-derived docosahexaenoic acid metabolites, were identified initially in the retina;682;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;Knowledge of the significance of lipid signaling in the nervous system is being expanded by advances in experimental approaches;682;Understanding of the fundamental workings of the dendrites, which contain complex intracellular membranes rich in polyunsaturated;683;Arachidonic acid is widely implicated in signaling in brain, and research continues toward understanding the release of this fatty;683;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;During embryonic and postnatal development, and throughout adult life, many cells in the nervous system die;688;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;Adaptive apoptosis occurs in the developing and adult nervous system;689;Apoptosis occurs in acute neurological insults;690;Apoptosis occurs in neurodegenerative disorders;692;There are many triggers of apoptosis;693;Insufficient trophic support;6
93;Death receptor activation;693;DNA damage;693;Oxidative and metabolic stress;693;Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process;694;Several different changes in mitochondria occur during apoptosis;695;The postmitochondrial events of apoptosis include activation of the caspases;695;A widely used criterion for identifying a cell as apoptotic is nuclear chromatin condensation and fragmentation;695;Cells in the nervous system possess different mechanisms to prevent apoptosis;695;Neurotrophic factors, cytokines and cell adhesion molecules;695;Antiapoptotic proteins;696;Hormesis-based mechanisms;696;Antioxidants and calcium-stabilizing proteins;696;The morphological and biochemical characteristics of apoptosis are not always manifest in cells undergoing programmed cell ...;697;Apoptotic cascades can be triggered, and pre- and postmitochondrial events can occur, without the cell dying;697 14.5.3;Necrosis;697;Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates;697;There are few cell death triggers that are only capable of inducing either apoptosis or necrosis;697;Trauma;697;Energy failure/ischemia;697;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;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;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;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;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;Infections can damage nerves directly, via exotoxins, or by immune mechanisms;712;Peripheral nerve damage is a recognized complication of toxins (e.g., alchohol, heavy metals, hexacarbons, organophosphates;712;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;Myelin deficiency can result from failure of synthesis during development or from myelin breakdown after its formation;717;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;Nervous system damage in acquired demyelinating diseases is selectively against myelin or myelin-forming cells, but axons;717;Multiple sclerosis (MS) is the most common demyelinating disease of the CNS in humans;717;Diagnosis;717;Pathology;718;Gray matter lesions;718;Axonal and neuronal pathology;719;Biochemistry;719;Therapy;720;Etiology;720;Epidemiology and natural history of MS;720;Environmental factors;720;Genetics;721;Immunology;721;Perspectives for future research;721;Animal models are required to understand the pathogenesis
of MS and test the efficacy of possible therapeutic interventions;721;Viral models;721;Experimental allergic encephalomyelitis;722;Toxins;722;Other acquired disorders affecting CNS myelin have an immune-mediated or infectious pathogenesis;722;Acute disseminated encephalomyelitis;722;Progressive multifocal leukoencephalopathy;722;Some human peripheral neuropathies involving demyelination are immune mediated;722;Paraproteinemic polyneuropathy;723;GuillainBarré syndrome;723;Chronic inflammatory demyelinating polyneuropathy;724 15.2.3;Genetically Determined Disorders of Myelin;724;The human leukodystrophies are inherited disorders of CNS white matter;724;Lysosomal storage diseases;724;Other leukodystrophies;726;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;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;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;The capacity for remyelination depends upon the presence of receptive axons and sufficient myelin-forming cells;727;Spontaneous remyelination of lesions of MS is well documented, but remyelination is usually incomplete;728;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;Disrupting the delicate bala
nce of inhibitory and excitatory synaptic transmission can trigger the disordered, synchronous;731;Cellular mechanisms underlying hyperexcitability have been analyzed by electrophysiological studies of hippocampal slices;733;Normally the dentate granule cells of hippocampus limit excessive activation of their targets, the CA3 pyramidal cells;733;Analyses of afferents of dentate granule cells from epileptic animals reveal abnormal inhibitory and excitatory synaptic input;734;Axonal and dendritic sprouting lead to abnormal recurrent excitatory synaptic circuits among the dentate granule cells in epileptic brain;734;Epileptogenesis is the process by which a normal brain becomes epileptic;734;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;Many antiseizure drugs act on voltage-gated sodium channels to limit high-frequency, but not low-frequency, firing of neurons;736;Other antiseizure drugs enhance GABA-mediated synaptic inhibition;736;Other antiseizure drugs regulate a subset of voltage-gated calcium currents;737 15.3.4;Genetics of Epilepsy;738;Many forms of epilepsy have genetic determinants;738;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;Early onset familial AD;746;Apolipoprotein E in late-onset AD;746;Genome-wide screening in late-onset AD;747 15.4.3;Parkinsons Disease;748;Autosomal-dominant forms of PD;748;Autosomal-recessive forms of PD;748;Candidate-gene studies and genome-wide screening in PD;749 15.4.4;Dementia with Lewy Bodies;750;The genetics of DLB shows similarities with both
PD and AD;750 15.4.5;Frontotemporal Dementia;751;Genetic determinants of tau-positive FTLD;751;Genetic determinants of tau-negative FTLD;751 15.4.6;Amyotrophic Lateral Sclerosis;752;Familial ALS;752 15.4.7;Neurodegenerative Triplet Repeat Disorders;754;Huntingtons disease (HD);754 15.4.8;Creutzfeld-JaKob Disease and other Prion Diseases;755;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;An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid;763;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;Untreated aminoacidurias can cause brain damage in many ways, often through impairing brain energy metabolism;763;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;Treatment of aminoacidurias with a low-protein diet may influence brain chemistry;767;Imbalances of brain amino acids may hinder the synthesis of brain lipids, leading to a diminution in the rate of myelin formation;767;In many aminoacidurias, there may occur deficits in neurotransmitters and receptors, particularly the N-methyl-d-aspartate receptor;767;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;Maple syrup urine disease involves a congenital failure to oxidize the three branched-chain amino acids;767;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;Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase;768;The outlook for patients who are treated at an early age is favorable;769;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;Nonketotic hyperglycinemia results from the congenital absence of the glycine cleavage system, which mediates the interconversion of glycine and serine;769;Nonketotic hyperglycinemia causes a severe seizure disorder and profound brain damage;769;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;The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids;770;Homocystinuria is the result of the congenital absence of cystathionine synthase, a key enzyme of the transsulfuration pathway;772;Homocystinuria can be treated in some cases by the administration of pyridoxine (Vitamin B6), which is a cofactor for the cystathionine synthase reaction;772;Patients with homocystinuria are at risk for cerebrovascular and cardiovascular disease and thromboses;772;Prognosis is more favorable in the pyridoxine-responsive patients;772;Homocystinuria can occur when homocysteine is not remethylated back to form methionine;773;One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine;773;Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria;773;Cobalamin-c disease: remethylation of homocysteine to meth
ionine also requires an activated form of vitamin B12;773;Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration;774 15.5.6;The Urea Cycle Defects;774;The urea cycle is essential for the detoxification of ammonia;774;Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant;775;Carbamyl phosphate synthetase deficiency;775;N-Acetylglutamate synthetase deficiency;775;Ornithine transcarbamylase deficiency;775;Citrullinemia;775;Argininosuccinic aciduria;776;Arginase deficiency;776;Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle;776;Hyperornithinemia, hyperammonemia, homocitrullinuria;776;Lysinuric protein intolerance;776;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;The tripeptide glutathione is the major intracellular antioxidant;777;5-Oxoprolinuria: glutathione synthetase deficiency;777;.-Glutamylcysteine synthetase deficiency;777;.-Glutamyltranspeptidase deficiency;777;5-Oxoprolinase deficiency;777 15.5.8;Disorders of g-Aminobutyric Acid Metabolism;777;Congenital defects in the metabolism of .-aminobutyric acid have been described;777;Pyridoxine dependency;778;.-Aminobutyric acid transaminase deficiency;778;Succinic semialdehyde dehydrogenase deficiency;778 15.5.9;Disorders of N-Acetyl Aspartate Metabolism;778;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;The cell contains specialized organelles for the recycling of waste material: the lysosomes;780;Deficiency of a lysosomal enzyme causes the blockage of the corresponding metabolic pathway, leading to the accumulation of its undigested substrate;781;For most lysosomal storage diseases, definitive cures are not available;782;Lysosomal storage disorders are pleiotropic, depending on the mutation, the enzyme affected and the sites of accumulated products;782;Farber disease;782;Gaucher disease;782;Krabbe disease (globoid cell leukodystrophy);783;Metachromatic leukodystrophy (MLD);783;Fabry disease;784;GM2 gangliosidoses (TaySachs disease; Sandhoff disease and GM2 activator deficiency);784;NiemannPick disease, types A and B;785;NiemannPick disease type C (NPC);785;The mucopolysaccharidoses (MPS);785;Neuronal ceroid lipofuscinoses (NCLs);785 15.6.2;Peroxisomal Diseases;785;Peroxisomes are specialized organelles for metabolism of oxygen peroxide and of various lipids;785;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;Human diseases involving peroxisomal dysfunction were originally described as syndromes;786;Defects of peroxisomal biogenesis;786;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;Diseases of carbohydrate and fatty acid metabolism in muscle;788;One class of glycogen or lipid metabolic disorders in muscle is manifest as acute, recurrent, reversible dysfunction;788;Phosphorylase deficiency (McArdle disea
se, glycogenosis type V) exemplifies the glycogenoses causing recurrent muscle energy crises, with cramps, myalgia;788;Genetic defects of phosphorylase b kinase (PHK);788;Other glycolytic defects involving PFK, PGK, PGAM, and LDH have clinical and pathological features similar to McArdle disease;789;CPT II deficiency has clinical features similar to McArdle disease;791;Other beta-oxidation defects have clinical features similar to McArdle disease;791;A second class of disorders of glucose and fatty acid metabolism causes progressive weakness;791;Acid maltase deficiency (AMD) (glycogenosis type II);791;Debrancher enzyme deficiency (glycogenosis type III, Coris disease, Forbe disease);792;Branching enzyme deficiency (glycogenosis type IV; Andersens disease);792;Carnitine deficiency;792;Defects in adipose triglyceride lipase (ATGL);793;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;Diseases of carbohydrate and fatty acid metabolism in brain;795;Defective transport of glucose across the bloodbrain barrier is caused by deficiency in the glucose transporter protein;795;One class of carbohydrate and fatty acid metabolism disorders is caused by defects in enzymes that function in the brain;795;Debrancher enzyme deficiency;795;Branching enzyme deficiency;795;Phosphoglycerate kinase deficiency;796;Lafora disease;796;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;Fructose-1,6-bisphosphatase deficiency;796;Phosphoenolpyruvate carboxykinase (PEPCK) deficiency;796 15.6
.5.3.10;Pyruvate carboxylase deficiency;796;Biotin-dependent syndromes;797;Glycogen synthetase deficiency;797;Fatty acid oxidation defects;797 15.6.6;Diseases of Mitochondrial Metabolism;797;Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system;797;Mitochondrial DNA is inherited maternally;798;The genetic classification of mitochondrial diseases divides them into three groups;799;Defects of nuclear DNA;799;Defects of communication between nDNA and mtDNA can also cause mitochondrial diseases;800;Defects in genes controlling mtDNA translation;800;The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism;800;Defects of mitochondrial transport;800;Defects of substrate utilization;800;Defects of the Krebs cycle;801;Defects of oxidationphosphorylation Coupling;801;Abnormalities of the respiratory chain;801;Abnormalities of the respiratory chain: defects of complex I;801;Abnormalities of the respiratory chain: defects of complex II;802;Abnormalities of the respiratory chain: coenzyme Q10 (CoQ10) deficiency;802;Abnormalities of the respiratory chain: defects of complex III;802;Abnormalities of the respiratory chain: defects of complex IV;802;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;Nerve and muscle communicate through neuromuscular junctions;808;Acetylcholine acts as a chemical relay between the electrical potentials of nerve and muscle;810;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;The excitable apparatus of muscle is composed of membranous compartments;811;Myofibrils are designed and positioned to produce movement and force;811;Calcium couples muscle membrane excitation to filament contraction;812 15.7.3;Genetic Disorders of the Neuromuscular Junction;814;Congenital myasthenic syndromes impair the operation of the acetylcholine receptor;814;ChAT Deficiency;814;AChR Deficiency;814;Rapsyn deficiency;815;Slow channel syndrome;815;Fast channel syndrome;815;Acetylcholinesterase deficiency;815 15.7.4;Hereditary Diseases of Muscle Membranes;815;Mutations of the sodium channel cause hyperkalemic periodic paralysis and paramyotonia congenital;815;Hypokalemic periodic paralysis is due to calcium channel mutations;816;Abnormal potassium channels in Andersen syndrome cause more than periodic paralysis;816;Ribonuclear inclusions are responsible for the multiple manifestations of myotonic dystrophy;816;Congenital myotonia is caused by mutant Cl- channels;817;Malignant hyperthermia caused by mutant ryanodine receptor calcium release channels;817;Calcium channel mutations may also cause malignant hyperthermia;818;Brody disease is an unusual disorder of the sarcoplasmic reticulum calcium ATPase;818 15.7.5;Immune Diseases of Muscle Excitability;818;Myasthenia gravis is caused by antibodies that promote premature AChR degradation;818;Antibodies against MuSK mimic myasthenia gravis;818;Antibodies cause calcium channel dysfunction in Lambert-Eaton syndrome;819;Potassium channel antibodies in Isaac syndrome cause neuromyotonia;819 15.7.6;Toxins and Metabolites that Alter Muscular Excitation;820;Bacterial botulinum toxin blocks presynaptic ACh release;820;Snake, scorpion, spider, fis
h and snail peptide venoms act on multiple molecular targets at the neuromuscular junction;821;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;The disease is characterized clinically by weakness, muscle atrophy and spasticity affecting both upper and lower motor neurons;827;Although most cases ALS are sporadic, mutations in several genes may cause familial ALS;828;ALS1 is caused by mutant SOD1;828;ALS2 is linked to mutant Alsin;828;ALS4 is linked to mutations in a helicase gene;828;Angiogenic factors may be linked to ALS;828;Mutant dynactin p150Glued causes fALS;829;VAPB associated with ALS is a ligand for eph receptors;829;ALS is linked to two genes involved in RNA metabolism: TDP-43 and FUS;829;Mutations in OPTN were identified in several japanese patients with ALS;830;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;Interrupting the communication between the motor neuron cell body and axon by transection, crush or avulsion induces motor neuron injury;831;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;Hereditary canine spinal muscular atrophy (HCSMA) is a naturally occurring mutation that produces motor neuron disease;831;Some transgenic mice expressing wild-type or mutant NF genes develop motor neuron disease and neurofibrillary pathology;832;fALS-linked mutant SOD1 mice reproduce many of the clinical and pathological features of ALS;832;Lines
of mice harboring other mutant genes may also develop an ALS-like phenotype;832;Mutant dynactin p150glued transgenic mice have MND-like pathology;833;Mutant tubulin-specific chaperone E transgenic mice exhibit progressive motor neuropathy;833;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;Vascular endothelial growth factor (VEGF) influences the growth and permeability of blood vessels;833;The molecular mechanisms whereby mutant SOD1 causes selective motor neuron death have yet to be defined;833;Is the toxicity of mutated SOD1 cell-autonomous?;833;Expression of GLT1 is implicated as a possible cofactor;833;Mutation-induced conformational effects and copper oxidative toxicity have been implicated;834;Accumulating evidence supports the view that fALS-associated mutants facilitate misfolding of wild-type SOD1;834;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;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;Advances in laboratory measurements and imaging are of value in establishing the diagnosis of AD;841;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;APP Mutations are Linked to fAD;842;Mutations in PS1 and PS2 ar
e Linked to fAD;842;Multiple neurotransmitter circuits and brain networks are damaged in AD;842;Neuritic plaques, one of the pathological hallmarks of AD, are composed of swollen neurites, extracellular deposits of Aß 40-42 peptides derived from;843;Neurofibrillary tangles (NFT), another characteristic feature of AD, are composed of intracellular bundles of paired helical filaments (PHF), which represent;843;Aspartyl proteases carry out the ß- and g-secretase cleavages of APP to generate Aß peptides;844;Transgenic strategies have been used to create models of Aß amyloidosis and tauopathies;845;Gene targeting approaches have identified and validated targets for therapy;846;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;The human synuclein family consists of three members;855;Synucleins are lipid-binding proteins;855 15.10.3;Parkinsons Disease and Other Lewy Body Diseases;856;SNCA mutations cause familial Parkinsons disease;856;Lewy body filaments are made of a-synuclein;856;The development of a-synuclein pathology is not random;857;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;Rodents and primates;858;Flies, worms and yeasts;859 15.10.7;SynucleinopathiesOutlook;859 15.10.8;Microtubule-Associated Protein Tau;859;Six tau isoforms are expressed in adult human brain;859;Tau is a phosphoprotein;860 15.10.9;Tau and Alzheimers Disease;860;The paired helical filament is made of tau protein;860;Filamentous tau is hyperphosphorylated;860;The development of t
au pathology is not random;861 15.10.10;Other Tauopathies;861;Other taupathies include progressive supranuclear palsy, corticobasal degeneration and Picks disease;861 15.10.11;MAPT Mutations Causing Tauopathy;861;FTD is characterized by atrophy of the frontal and temporal lobes of the cerebral cortex, with additional subcortical changes;861;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;Rodents and fish;863;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;CAG repeat expansions are responsible for nine inherited neurodegenerative disorders;869;Normal functions of polyglutamine disease proteins;870 15.11.2;Expanded Polyglutamine Tracts Promote Protein Misfolding to Drive Neurotoxicity;870;Disease-length polyglutamine tracts adopt a novel, toxic conformation;870;Polyglutamine disease proteins form aggregates visible at the light microscope level;870;Polyglutamine disease proteins exist as misfolded monomers, oligomers and protofibrils;871;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;Are polyglutamine tracts substrates for the ubiquitin-proteasome system and autophagy pathways?;871;Autophagy pathway involvement in polyglutamine neurodegeneration;872;Evidence for autophagy dysfunction in the polyglutamine repeat diseases;874 15.11.4;The Importance of Normal Function in the Polyglutamine Repeat Diseases;874;Interference with ataxin-7s function as a transcription regulato
ry protein in SCA7;874;Ataxin-1 protein complex associations account for SCA1 disease pathogenesis;874;Post-translational modifications as determinants of disease;874;Phosphorylation;874;Acetylation;875;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;RNA interference knock-down and antisense oligonucleotide knock-down: two approaches;875;Indiscriminate gene silencing;876;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;The basal ganglia are components of larger circuits;881;Involvement of the basal ganglia in movement control;882;Multiple neurotransmitter systems are found in the basal ganglia;882;GABA;882;Glutamate;883;Acetylcholine;883;Dopamine;884;Dopamineacetylcholine balance;885;Adenosine, cannabinoid and neuropeptides function in the basal ganglia;885 15.12.2;Disorders that Involve Basal Ganglia Dysfunction;886;Parkinsons disease is a hypokinetic movement disorder;886;Pathology;886;Etiology;886;Animal models;887;Pathophysiology;887;Symptomatic drug treatment of PD;888;Surgical therapy;889;Neuroprotective treatment of PD;889;Huntingtons disease is a hyperkinetic movement disorder;890;Genetic and molecular aspects;890;Animal models;890;Treatment;890;Dystonia is a disorder with involuntary movements;891;Etiology and classification;891;Pathophysiology;892;Treatment;892;Neuropsychiatric disorders;892;Drugs affecting the basal ganglia;893;
Dopamine depleting agents;893;Dopamine receptor blocking agents;893;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;Discovery of the prion protein;898;Prion protein is encoded by the host;898;Aberrant metabolism of the prion protein is the central feature of prion disease;898 15.13.3;Animal Prion Diseases;898;Scrapie and BSE;898;Other animal prion diseases;899 15.13.4;Human Prion Diseases;899;Human prion disease most commonly presents itself sporadically;899;Pathogenic mutations in the prion protein gene cause inherited prion disease;899;Acquired human prion diseases include kuru and variant CJD;900;Prion protein polymorphism contributes genetic susceptibility to prion disease;900;Human prion diseases are clinically heterogeneous;900 15.13.5;Prion Disease Pathology and Pathogenesis;901;Peripheral pathogenesis involves the lymphoreticular system;901;Prion disease produces characteristic pathology in the central nervous system;901 15.13.6;The Protein-Only Hypothesis of Prion Propagation;902;Prion propagation involves conversion of PrPC to PrPSc;902 15.13.7;Characterization of PrPC;902;PrPC has a predominantly alpha-helical conformation;902;Reverse genetics approaches to studying PrPC;903;The function of PrPC remains unknown;903;PrP knockout mice have subtle abnormalities;903 15.13.8;Characterization of PrPSc;904;PrPSc has a predominantly beta-sheet conformation;904;Prion structure remains unknown;904;In vitro generation of alternative PrP conformations and prion infectivity;905 15.13.9;The Molecular Basis of Prion Strain Diversity;905;Prion strain diversity appears to be encoded by PrP itself;905;Distinct PrPSc types are seen in human prion disease;905;Difficulties in defining human prion strains;906 15.13.10;Prion Transmission Barriers;907;Prion transmission between species is limited by a barrier;907;Both PrP sequence and prion strain type influence prion transmission barriers;907;A conformational selection model of prion transmission barriers;907;Subclinical forms of prion disease pose a risk to public health;907;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;The visual system is composed of unique structures optimized for collection, detection and processing of visual information;914;The retina is composed of highly organized neuronal sublayers;915;The ganglion cell axons of the optic nerve carry visual signals from the retina to the brain;915;The eye develops as an outcropping of the developing brain;916 16.1.2;Photoreceptors and Phototransduction;917;Photoreceptors are polarized cells, with specialized primary cilia, outer segments, devoted to phototransduction;917;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;Recovery of the dark current after light stimulation is a multistep process mediated by Ca2+ and proteins exerting negative regulation;919;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;Secondary neurons respond to changes in glutamate release by rods and cones;922;ON and OFF bipolar cells use different types of rece
ptors and response mechanisms;922;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;Rhodopsin regeneration requires a complex series of enzyme-catalyzed reactions in photoreceptors and RPE;923;Cones use a visual cycle distinct from that of rods to regenerate pigments;924;Retinal pigemented epithelial (RPE) cells promote disk membrane turnover by phagocytosis;924 16.1.5;Retinal Neurodegeneration;924;Defects in genes essential for functions of photoreceptors cause retinal degeneration;924;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;The mammalian olfactory system possesses enormous discriminatory power;929;The initial events in olfaction occur in a specialized olfactory neuroepithelium;930;The identification and cloning of genes encoding odorant receptors helped to reveal organizational principles of odor coding;930;Odor discrimination involves a very large number of different odorant receptors, each responsive to a small set of odorants;931;The information generated by hundreds of different receptor types must be organized to achieve a high level of olfactory discrimination;931;Zonal Expression of Olfactory Receptors;932;Convergence of Sensory Neurons Onto a few Glomeruli in the Olfactory Bulb;932;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;Odorant recognition initiates a second-messenger cascade leading to the depolarization of the neuron and the generation of action potentials;932;Negative feedback processes mediate adaptation of the ol
factory transduction apparatus to prolonged or repetitive stimulation;933;Subpopulations of OSNs use alternative olfactory transduction mechanisms;934;The vomeronasal organ is an accessory chemosensing system that plays a major role in the detection of semiochemicals;935;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;Multiple senses, including taste, contribute to our total perception of food;936;Taste receptor cells are organized into taste buds;937;Sensory afferents within three cranial nerves innervate the taste buds;937;Sweet, bitter and umami taste involve G protein-coupled receptors;937;Type 1 Taste Receptors (T1Rs) Recognize Sweet and Umami Stimuli;937;Type 2 Taste Receptors (T2Rs) Mediate Responses to Bitter-Tasting Stimuli;938;T1Rs and T2Rs also Have Important Functions Outside the Gustatory System;938;Sweet, bitter and umami tasting stimuli are transduced by a G-proteincoupled signaling cascade;938;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;Mechanotransduction is of great utility for all organisms;941;Models for mechanotransduction allow comparison of mechanoreceptors from many organisms and cell types;941 16.3.2;Non-Vertebrate Model Systems;942;Worm mechanoreceptors use a transduction cascade that depends on epithelial sodium channels (ENaC);943;Fly mechanoreceptors use molecules similar to those of hair cells;943 16.3.3;Hair Cells;943;Hair cells are the sensory cells of the auditory and vestibular systems;943;Hair cells are exposed to unusual extracellular fluids and potentials;944;Mechanic
al transduction depends on activation of ion channels linked to extracellular and intracellular structures;945;Some of the molecules responsible for transduction have been identified;946;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;Vestibular organs detect head rotation and linear acceleration;948;Hair bundles display varying morphology and physiology;948 16.3.6;Hearing: Cochlea;948;The cochlea detects sound and is tonotopically organized;948;High-frequency sound detection requires specialized structures and molecules;950;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;Primary sensory neurons are located in the dorsal root ganglions (DRG) of spinal nerves and the semilunar ganglions of the trigeminal nerves;954;Receptor profiles define the response modalities of nociceptors;954;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;Nociceptive information enters the dorsal horn of the spinal cord;955;Signals are modulated by spinal interneurons;955 16.4.4;Brainstem, Thalamus and Cortex;956;Nuclei in the brainstem and thalamus, and distinct cortical areas are the major projection targets for nociceptive information;956;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;Tissue injury produces an inflammatory soup of signaling molecules;959;Molecular mechanisms involved in peripheral sensitization;959;Central sensitization;959;Prolon
ged homosynaptic facilitation;960 16.4.8;Neuropathic Pain;961;Paradoxically, nervous system injury may produce not only sensory loss but also chronic pain;961;Spontaneous discharges and enhanced excitability of sensory neurons;961;Allodynia signals a crossover of sensory modalities;961;Central sensitization and descending facilitation;962;Disinhibition;962;Immune response to nerve injury;963 16.4.9;Genetic Factors;964;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;The hypothalamic releasing factors regulate release of the anterior pituitary trophic hormones;971;Secretion of pituitary hormones is responsive to behavior and effects of experience;971;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;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;Steroid hormones are divided into six classes, based on physiological effects: estrogens, androgens, progestins, glucocorticoids, mineralocorticoids and vitamin D;974;Some steroid hormones are converted in the brain to more active products that interact with receptors;974;The Aromatization of Testosterone;975;Vitamin D;976;Genomic receptors for steroid hormones have been clearly identified in the nervous system;976 17.1.5;Intracellular Steroid Receptors: Properties and Topography;978;Steroid hormone receptors are phosphoproteins that have a DNA-binding dom
ain and a steroid-binding domain;978;Estradiol;978;Progesterone;978;Androgen;979;Glucocorticoid;979;Mineralocorticoid;979;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;During development, steroid-hormone receptors become evident in target neurons of the brain;981;The response of neural tissue to damage involves some degree of structural plasticity, as in development;982;Activation and adaptation behaviors may be mediated by hormones;982;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;The Penfield studies;989;Amnesia patients and the role of the temporal lobe in memory;989 17.2.2;Divisions of Memory;990;Declarative memory vs. procedural memory;990;Short-term memory vs. long-term memory;990 17.2.3;Molecular Mechanisms of Learning;990;Hebbs rule and experimental models for synaptic plasticity;990;The NMDA receptor and LTP induction;991;Molecular mechanisms underlying the early- and late-phase expressions of LTP;992;Other forms of synaptic plasticity: Long-term depression (LTD) and NMDA receptor-independent LTP;993;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;Retrograde amnesia and post-learning consolidation by the hippocampus;996 17.2.5;Neural Population-Level Memory Traces and Their Organizing Principles;996;In search of memorys neural code;996;Visualizing network-level real-time memory traces;999 17.
2.5.3;Identification of neural cliques as real-time memory coding units;999;General-to-specific feature-encoding neural clique assemblies;999;Concept cells in the hippocampus: nest cells and Halle Berry cells;1000;Differential reactivations within episodic cell assemblies underlying selective memory consolidation;1000;The generalization function of the hippocampus;1002;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;The daily cycle of sleep and wakefulness is one of the most fundamental aspects of human biology;1008;The functions of sleep remain enigmatic;1008;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;Compared to other medical specialties, sleep disorders medicine has a very short history;1009;Understanding the neurochemical regulation of sleep is essential for advancing sleep disorders medicine;1010 17.3.3;Monoamines;1011;Serotonin, norepinephrine and histamine are major components of the ascending reticular activating system, and each of these neurotransmitters plays a unique role in;1011;Norepinephrine promotes arousal during normal wakefulness, and augments arousal during periods of stress and in response to psychostimulant drugs;1011;Serotonin has a biphasic effect on sleep;1011;Histamine levels are greater during wakefulness than during sleep, consistent with the fastest firing rates of histamine-containing neurons occurring during wakefulness;1012;Sleep disorders and depression are linked by monoamines;1012 17.3.4;Acetylcholine;1012;Acetylcholine contributes significantly to the generation of REM sleep and wakefulness;1012;Evidence t
hat pontine cholinergic neurotransmission promotes the generation of REM sleep comes from many studies using a wide range of approaches;1013;Acetylcholine, depression, REM sleep and pain;1013 17.3.5;Dopamine;1013;Unlike other monoaminergic neurons, dopaminergic cells do not cease firing during REM sleep;1013;Restless legs syndrome, Parkinsons disease and sleep;1014 17.3.6;Hypocretins/Orexins;1014;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;Hypocretins promote normal wakefulness;1015;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;γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and drugs that enhance transmission at GABAA;1015;The effects of GABA on sleep and wakefulness vary as a function of brain region;1016;GABAergic transmission in the pontine reticular formation contributes to the regulation of sleep and wakefulness;1016;Clinical implications of GABAergic transmission for sleep;1016;Glutamate is the major excitatory neurotransmitter in the brain, yet elucidating the role of glutamate in regulating sleep and wakefulness has been challenging;1016;Effects of glutamate on sleep and wakefulness vary as a function of brain region;1017;Glutamate modulates the interaction between sleep, depression and pain;1017 17.3.8;Adenosine;1018;Adenosine is an endogenous sleep factor that mediates the homeostatic drive to sleep;1018;Adenosine inhibits wakefulness and promotes sleep via multiple mechanisms;1018;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;Schizophrenia is a severe, chronic disabling mental disorder;1025;Schizophrenia is characterized by three independent symptom clusters;1026;Schizophrenia is a disorder of complex genetics;1026;Current treatment of schizophrenia relies on atypical antipsychotic drugs;1026 17.4.2;Brain Imaging;1028;Brain imaging studies provide unequivocal evidence that schizophrenia is a brain disease;1028;Functional imaging studies have consistently shown corticolimbic abnormalities in schizophrenia;1028 17.4.3;Cellular and Molecular Studies;1029;The dopamine hypothesis has dominated schizophrenia research for 40 years;1029;Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia;1030;GABAergic neurons are also implicated in schizophrenia;1032;The cholinergic system has also been implicated in schizophrenia;1033;Some intracellular signal transduction molecules are reduced in schizophrenia;1033;Proteins involved in fundamental structure and function of neurons are decreased in schizophrenia;1033;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;ASDs are defined by three independent symptom clusters;1037;Autism is heterogeneous from a behavioral, neurobiological and genetic standpoint;1038;The autism field is moving towards a more dimensional and less categorical perspective;1038;Current pharmacological treatment of autism is usually effective for only certain aspects of the symptom constellation;1039 17.5.2;Genetic Studies;1039;The genetics of autism are complex, heterogenetic and, in most cases, polygenetic;1039;Roles of epistasis and emergenesis
are unclear;1039 17.5.3;Neurochemical Studies;1039;Limited postmortem brain data are available and are not definitive;1039;Dopaminergic functioning appears normal;1040;Stress response systems: basal functioning is normal, but hyperreactive in autism;1040;The serotonin system: a focus on platelet hyperserotonemia and the 5-HT2 receptor;1040;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;Serotonergic system;1047;Noradrenergic system;1048;Dopaminergic system;1049;Cholinergic system;1049;Glutamatergic system;1049;GABAergic system;1049;Cortical-hypothalamic-pituitary-adrenal axis;1049;Thyroid axis;1049;Other neuropeptides;1050;Brain growth factors;1050;Substance P;1050 17.6.3;Neuroanatomical and Neuropathological Correlates of Mood Disorders;1050;Functional neuroimaging methods;1050;Stress, glucocorticoids and neuroplasticity;1051 17.6.4;Intracellular Signaling Pathways;1051;The G-proteinsubunit/cyclic adenosine monophosphate (CAMP)generating signaling pathway;1052;The protein kinase C signaling pathway;1052;Glycogen synthase kinase;1052;BDNF and Bcl-2;1054;Intracellular calcium signaling;1054 17.6.5;Anxiety Disorders;1055 17.6.6;The Neurochemistry of Fear and Anxiety;1055;Noradrenergic systems;1055;Serotonergic system;1056;GABAergic system;1056;CRH and stress axes;1057;Other neuropeptides;1057;Neuropeptide Y;1057;Cholecystokinin;1057;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;Addiction is characterized by compulsive drug use, despite severe negative consequences;1063;Many forces may drive compulsive drug use;1063 17.7.2;Neuronal Circuitry of Addiction;1063;Natural reinforcers and drugs of abuse increase dopamine transmission;1063;Many neuronal circuits are ultimately involved in addiction;1065 17.7.3;Opiates;1066;Opiates are drugs derived from opium, including morphine and heroin;1066;There are three classical opioid receptor types;1066;Opioid receptors generally mediate neuronal inhibition;1066;Chronic opiate treatment results in complex adaptations in opioid receptor signaling;1066;Opiate addiction involves multiple neuronal systems;1066;Upregulation of the cyclic AMP (cAMP) second-messenger pathway is a well-established molecular adaptation;1067;There are two main treatments for the opiate withdrawal syndrome;1068;Endogenous opioid systems are an integral part of the reward circuitry;1068 17.7.4;Psychomotor Stimulants;1068;This drug class includes cocaine and amphetamine derivatives;1068;Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants;1068;Cocaine and amphetamines initiate neuronal adaptations by repeatedly elevating monoamine levels but ultimately affect glutamate and other transmitter systems;1069;Dopamine receptor transmission involves multiple signaling cascades and is altered in psychomotor stimulant addiction;1070 17.7.5;Cannabinoids (Marijuana);1070;Marijuana and hashish are derivatives of the cannabis sativa plant;1070;Cannabinoid effects in the CNS are mediated by the CB1 receptor;1070;Endocannabinoids are endogenous liga
nds for the CB1 receptor;1071;Endocannabinoids serve as retrograde messengers that regulate synaptic plasticity;1071;There are many similarities between endogenous opioid and cannabinoid systems;1073 17.7.6;Nicotine;1073;Nicotine is responsible for the highly addictive properties of tobacco products;1073;Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR);1073;The ventral tegmental area (VTA) is a critical site for nicotine action;1073 17.7.7;Ethanol, Sedatives and Anxiolytics;1074;Alcoholism is a chronic relapsing disorder;1074;Ethanol interacts directly with ligand-gated and voltage-gated ion channels;1074;Multiple neuronal systems contribute to the reinforcing effects of ethanol;1074;Pharmacotherapies for alcoholism are improving;1074;Barbiturates and benzodiazepines are used to treat anxiety;1075 17.7.8;Hallucinogens and Dissociative Drugs;1075;Hallucinogens produce an altered state of consciousness;1075;Phencyclidine (PCP) is a dissociative drug;1075 17.7.9;Addiction And Neuronal Plasticity Share Common Cellular Mechanisms;1076;Drugs of abuse rewire neuronal circuits by influencing synaptic plasticity;1076;Drugs of abuse have profound effects on transcription factors and gene expression;1076;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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EAN: 9780080959016
Untertitel: Principles of Molecular, Cellular, and Medical Neurobiology. 200:Adobe eBook. Sprache: Englisch.
Verlag: Elsevier Science
Erscheinungsdatum: November 2011
Seitenanzahl: 1120 Seiten
Format: epub eBook
Kopierschutz: Adobe DRM
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