Albers / Price / Brady Basic Neurochemistry

Principles of Molecular, Cellular, and Medical Neurobiology
8. Auflage 2011
ISBN: 978-0-08-095901-6
Verlag: Elsevier Science & Techn.
Format: EPUB
Kopierschutz: Adobe DRM (»Systemvoraussetzungen)

E-Book, Englisch, 1120 Seiten

Basic Neurochemistry, Eighth Edition, is the updated version of the outstanding and comprehensive classic text on neurochemistry. For more than forty years, this text has been the worldwide standard for information on the biochemistry of the nervous system, serving as a resource for postgraduate trainees and teachers in neurology, psychiatry, and basic neuroscience, as well as for medical, graduate, and postgraduate students and instructors in the neurosciences. The text has evolved, as intended, with the science. This new edition continues to cover the basics of neurochemistry as in the earlier editions, along with expanded and additional coverage of new research from intracellular trafficking, stem cells, adult neurogenesis, regeneration, and lipid messengers. It contains expanded coverage of all major neurodegenerative and psychiatric disorders, including the neurochemistry of addiction, pain, and hearing and balance; the neurobiology of learning and memory; sleep; myelin structure, development, and disease; autism; and neuroimmunology. - Completely updated text with new authors and material, and many entirely new chapters - Over 400 fully revised figures in splendid color - 61 chapters covering the range of cellular, molecular and medical neuroscience - Translational science boxes emphasizing the connections between basic and clinical neuroscience - Companion website at http://elsevierdirect.com/companions/9780123749475

Autoren/Hrsg.

Albers, R. Wayne

Price, Donald L.

Brady, Scott

Siegel, George

Inhaltsverzeichnis

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
10.1.2.1;Diverse cell types comprising the nervous system interact to create a functioning brain;29
10.1.3;Neurons: Common Elements and Diversity;29
10.1.3.1;The classic image of a neuron includes a perikaryon, multiple dendrites and an axon;29
10.1.3.2;Although neurons share common elements with other cells, each component has specialized features;31
10.1.3.3;The axon compartment comprises the axon hillock, initial segment, shaft and terminal arbor;34
10.1.3.4;Dendrites are the afferent components of neurons;34
10.1.3.5;The synapse is a specialized junctional complex by which axons and dendrites emerging from different neurons intercommunicate;35
10.1.4;Macroglia: More than Meets the Eye;36
10.1.4.1;Virtually nothing can enter or leave the central nervous system parenchyma without passing through an astrocytic interphase;36
10.1.4.2;Oligodendrocytes are myelin-producing cells in the central nervous system;38
10.1.4.3;The schwann cell is the myelin-producing cell of the peripheral nervous system;38
10.1.5;Microglia;40
10.1.5.1;The microglial cell plays a role in phagocytosis and inflammatory responses;40
10.1.5.2;Ependymal cells line the brain ventricles and the spinal cord central canal;41
10.1.6;Blood–Brain Barriers and the Nervous System;41
10.1.6.1;Homeostasis of the central nervous system (CNS) is vital to the preservation of neuronal function;41
10.1.6.2;The BBB and BCSFB serve a number of key functions critical for brain function;42
10.1.6.3;Evolution of the blood–brain barrier concept;43
10.1.7;The Neurovascular Unit Includes Multiple Components;43
10.1.7.1;The lumen of the cerebral capillaries that penetrate and course through the brain tissue are enclosed by BECs interconnected by TJ;43
10.1.7.2;The basement membrane (BM)/basal lamina is a vital component of the BBB;44
10.1.7.3;Astrocytes contribute to the maintenance of the BBB;44
10.1.7.4;Pericytes at the BBB are more prevalent than in other capillary types;44
10.1.7.5;Brain endothelial cells restrict the transport of many substances while permitting essential molecules access to the brain;44
10.1.7.6;There are multiple transporters and transport processes for bidirectional transport at the BBB;46
10.1.7.7;Lipid solubility is a key factor in determining the permeability of a substance through the BBB by passive diffusion;46
10.1.7.8;The BBB expresses solute carriers to allow access to the brain of molecules essential for metabolism;47
10.1.7.9;Receptor-mediated transcytosis (RMT) is the primary route of transport for some essential peptides and signaling molecules;47
10.1.7.10;ATP-binding cassette transporters (ABC) on luminal membranes of the BBB restrict brain entry of many molecules;47
10.1.7.11;During development, immune-competent microglia develop and reside in the brain tissue;48
10.1.7.12;There is increasing evidence of BBB dysfunction, either as a cause or consequence, in the pathogenesis of many diseases affecting the CNS;48
10.1.7.13;The presence of an intact BBB affects the success of potentially beneficial therapies for many CNS disorders;48
10.1.8;Acknowledgements;48
10.1.9;References;50
10.2;2. Cell Membrane Structures and Functions;51
10.2.1;Phospholipid Bilayers;51
10.2.1.1;Cells are bounded by proteins arrayed in lipid bilayers;51
10.2.1.2;Amphipathic molecules can form bilayered lamellar structures spontaneously if they have an appropriate geometry;52
10.2.2;Membrane Proteins;53
10.2.2.1;Membrane integral proteins have transmembrane domains that insert directly into lipid bilayers;53
10.2.2.2;Many transmembrane proteins that mediate intracellular signaling form complexes with both intra- and extracellular proteins;54
10.2.2.3;Membrane associations can occur by selective protein binding to lipid head groups;54
10.2.3;Biological Membranes;54
10.2.3.1;The fluidity of lipid bilayers permits dynamic interactions among membrane proteins;54
10.2.3.2;The lipid compositions of plasma membranes, endoplasmic reticulum and golgi membranes are distinct;56
10.2.3.3;Cholesterol transport and regulation in the central nervous system is isolated from that of peripheral tissues;56
10.2.3.4;In adult brain most cholesterol synthesis occurs in astrocytes;56
10.2.3.5;The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling;57
10.2.3.6;The structure and roles of membrane microdomains (lipid rafts) in cell membranes are under intensive study but many aspects are still unresolved;58
10.2.3.7;Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton;59
10.2.3.8;The spectrin–ankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membrane…;59
10.2.3.9;Interaction of rafts with the cytoskeleton is suggested by the results of video microscopy;60
10.2.4;References;63
10.3;3. Membrane Transport;65
10.3.1;Introduction;66
10.3.2;Primary Active Transport (P-Type) Pumps;66
10.3.3;Na,K-Adenosinetriphosphatase (Na,K-ATPase);67
10.3.3.1;The reaction mechanism of Na,K-ATPase illustrates the mechanism of P-type pumps;67
10.3.3.2;Molecular structures of the catalytic subunits in the P-type transporters are similar;68
10.3.3.3;The active Na,K-ATPase is a heterodimer consisting of a catalytic a subunit and an accessory ß subunit;68
10.3.3.4;The a-subunit isoforms are expressed in a cell- and tissue-specific manner;68
10.3.3.5;The ß subunits are monotopic glycoproteins and exhibit some characteristics of cell adhesion molecules;68
10.3.3.6;The Na pump has associated . subunits;69
10.3.3.7;A major fraction of cerebral energy production is consumed by the Na,K pump;70
10.3.3.8;Na,K-ATPase Expression patterns change with development, aging and dementia;70
10.3.3.9;Na,K pump content in plasmalemma is regulated by its rapid endocytic–exocytic cycling;70
10.3.3.10;The distributions of a-subunit isoforms provide clues to their different physiological functions;70
10.3.3.11;Regulatory factors direct the trafficking of Na,K-ATPase during its synthesis;71
10.3.3.12;The Na,K-ATPase/Src complex functions as a signal receptor for cardiotonic steroids (CTS);71
10.3.3.13;Domain-specific interactions make the Na,K-ATPase an important scaffold in forming signaling microdomains;73
10.3.4;Ca Adenosinetriphosphatases and Na,Ca Antiporters;73
10.3.5;The Primary Plasma Membrane Ca Transporter (PMCA);73
10.3.5.1;PMCA is a plasmalemma P-type pump with high affinity for Ca2+;73
10.3.6;Smooth Endoplasmic Reticulum Calcium Pumps (SERCA);73
10.3.6.1;SERCA, another P-type Ca pump, was first identified in sarcoplasmic reticulum;73
10.3.6.2;High-resolution structural data exist for the SERCA1a Ca pump;73
10.3.7;Other P-Type Transporters;75
10.3.7.1;P-type copper transporters are important for neural function;75
10.3.8;V0V1 Proton Pumps;75
10.3.8.1;The V0V1-ATPase pumps protons into golgi-derived organelles;75
10.3.9;ATP-Binding Cassettes;75
10.3.9.1;The ABC transporters are products of one of the largest known gene superfamilies;75
10.3.9.2;The Three-dimensional structures of several ABC transporters from prokaryotes have been determined;75
10.3.9.3;ABCA1 translocates cholesterol and phospholipids outward across the plasma membrane;76
10.3.9.4;The multidrug-resistance proteins (MDR) can ‘flip’ amphipathic molecules;77
10.3.10;Secondary Active Transport;77
10.3.10.1;Brain capillary endothelial cells and some neurons express a Na-dependent D-glucose symporter;77
10.3.10.2;Neurotransmitter sodium symporters (NSS) effect the recovery of neurotransmitters from synaptic clefts;77
10.3.10.3;There are two distinct subfamilies of neurotransmitter sodium symporters;77
10.3.10.4;The SLC6 subfamily of symporters for amino acid transmitters and biogenic amines is characterized by a number of shared structural features;77
10.3.10.5;SLC1 proteins encompass glutamate symporters as well as some amino- and carboxylic-acid transporters expressed in bacteria;78
10.3.10.6;The glutamate symporters in brain are coded by five different but closely related genes, SLC1A1–4 and SLC1A6;78
10.3.10.7;Failure of regulation of glutamate concentration in its synaptic, extracellular and cytosol compartments leads to critical pathology;79
10.3.10.8;Choline transporter: termination of the synaptic action of acetylcholine is unique among neurotransmitters;79
10.3.10.9;Packaging neurotransmitters into presynaptic vesicles is mediated by proton-coupled antiporters;79
10.3.11;General Physiology of Neurotransmitter Uptake and Storage;80
10.3.12;The Cation Antiporters;80
10.3.12.1;Na,Ca exchangers are important for rapidly lowering high pulses of cytoplasmic Ca2+;80
10.3.12.2;Na,K-ATPase a subunits are coordinated with Na,Ca antiporters and Ca pumps;80
10.3.12.3;The overall mechanism for regulation of cytosolic Ca2+ is complex;80
10.3.13;The Anion Antiporters;81
10.3.13.1;Anion antiporters comprising the SLC8 gene family all transport bicarbonate;81
10.3.13.2;Intracellular pH in brain is regulated by Na,H antiporters, anion antiporters and Na,HCO3 symporters;81
10.3.14;Facilitated Diffusion: Aquaporins and Diffusion of Water;81
10.3.14.1;Simple diffusion of polar water molecules through hydrophobic lipid bilayers is slow;81
10.3.14.2;Crystallographic and architectural data are available for AQP1 and AQP4;82
10.3.14.3;The aquaporins found in brain are AQP1, 4 and 9;82
10.3.14.4;In astrocytic perivascular endfeet membranes, AQP4 is anchored to the dystrophin complex of proteins;82
10.3.14.5;AQP4 exists in astrocyte membranes and is coordinated with other proteins with which its function is integrated;82
10.3.14.6;Rapid diffusion of K+ and H2O from Neuronal extracellular space by astroglia is critical to brain function;83
10.3.14.7;Short-term regulation of AQP4 may result from phosphorylation of either of two serine residues;83
10.3.15;Facilitated Diffusion of Glucose and Myoinositol;83
10.3.15.1;Facilitated diffusion of glucose across the blood–brain barrier is catalyzed by GLUT-1, -2 and -3;83
10.3.15.2;HMIT is an H-coupled myoinositol symporter;84
10.3.16;References;85
10.4;4. Electrical Excitability and Ion Channels;88
10.4.1;Membrane Potentials and Electrical Signals in Excitable Cells;89
10.4.1.1;Excitable cells have a negative membrane potential;89
10.4.1.2;Real cells are not at equilibrium;90
10.4.1.3;Transport systems may also produce membrane potentials;90
10.4.1.4;Electrical signals recorded from cells are of two types: stereotyped action potentials and a variety of slow potentials;90
10.4.2;Action Potentials in Electrically Excitable Cells;91
10.4.2.1;During excitation, ion channels open and close and a few ions flow;91
10.4.2.2;Gating mechanisms for Na+ and K+ channels in the axolemma are voltage dependent;91
10.4.2.3;The action potential is propagated by local spread of depolarization;92
10.4.2.4;Membranes at nodes of ranvier have high concentrations of Na+ channels;92
10.4.3;Functional Properties of Voltage-Gated Ion Channels;92
10.4.3.1;Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane;92
10.4.3.2;Voltage-dependent gating requires voltage-dependent conformational changes in the protein component(s) of ion channels;93
10.4.3.3;Pharmacological agents acting on ion channels help define their functions;93
10.4.4;The Voltage-Gated Ion Channel Superfamily;94
10.4.4.1;Na+ channels were identified by neurotoxin labeling and their primary structures were established by cDNA cloning;94
10.4.4.2;Ca2+ channels have a structure similar to Na+ channels;96
10.4.4.3;Voltage-gated K+ channels were identified by genetic means;96
10.4.4.4;Inwardly rectifying K+ channels were cloned by expression methods;96
10.4.5;The Molecular Basis for Ion Channel Function;96
10.4.5.1;Much is known about the structural determinants of the ion selectivity filter and pore;96
10.4.5.2;Voltage-dependent activation requires moving charges;99
10.4.5.3;The fast inactivation gate is on the inside;99
10.4.6;Ion Channel Diversity;100
10.4.6.1;Na+ channels are primarily a single family;100
10.4.6.2;Three subfamilies of Ca2+ channels serve distinct functions;100
10.4.6.3;There are many families of K+ channels;101
10.4.6.4;More ion channels are related to the NaV, CaV and KV families;101
10.4.6.5;There are many other kinds of ion channels with different structural backbones and topologies;102
10.4.6.6;Ion channels are the targets for mutations that cause genetic diseases;102
10.4.7;Acknowledgments;102
10.4.8;References;104
10.5;5. Lipids;106
10.5.1;Introduction;106
10.5.2;Properties of Brain Lipids;107
10.5.2.1;Lipids have multiple functions in brain;107
10.5.2.2;Membrane lipids are amphipathic molecules;107
10.5.2.3;The hydrophobic components of many lipids consist of either isoprenoids or fatty acids and their derivatives;107
10.5.2.4;Isoprenoids have the unit structure of a five-carbon branched chain;107
10.5.2.5;Brain fatty acids are long-chain carboxylic acids that may contain one or more double bonds;107
10.5.3;Complex Lipids;108
10.5.3.1;Glycerolipids are derivatives of glycerol and fatty acids;108
10.5.3.2;In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone;110
10.5.4;Analysis of Brain Lipids;114
10.5.4.1;Chromatography and mass spectrometry are employed to analyze and classify brain lipids;114
10.5.5;Brain Lipid Biosynthesis;115
10.5.5.1;Acetyl coenzyme A is the precursor of both cholesterol and fatty acids;115
10.5.5.2;Phosphatidic acid is the precursor of all glycerolipids;119
10.5.5.3;Sphingolipids are biosynthesized by adding head groups to the ceramide moiety;121
10.5.6;Genes for Enzymes Catalyzing Synthesis and Degradation of Lipids;121
10.5.7;Lipids in the Cellular Milieu;123
10.5.7.1;Lipids are transported between membranes;123
10.5.7.2;Membrane lipids may be asymmetrically oriented;123
10.5.7.3;Some proteins are bound to membranes by covalently linked lipids;123
10.5.7.4;Lipids have multiple roles in cells;124
10.5.8;Summary;124
10.5.9;Acknowledgments;124
10.5.10;References;124
10.6;6. The Cytoskeleton of Neurons and Glia;126
10.6.1;Introduction;126
10.6.2;Molecular Components of the Neuronal Cytoskeleton;127
10.6.2.1;Along with the nucleus and mitochondria, the cytoskeleton is one of several biological structures that define eukaryotic cells;127
10.6.2.2;Microtubules act as both dynamic structural elements and tracks for organelle traffic;127
10.6.2.3;Neuronal and glial intermediate filaments provide support for neuronal and glial morphologies;131
10.6.2.4;Actin microfilaments and the membrane cytoskeleton play critical roles in neuronal growth and secretion;133
10.6.3;Ultrastructure and Molecular Organization of Neurons and Glia;135
10.6.3.1;A dynamic neuronal cytoskeleton provides for specialized functions in different regions of the neuron;135
10.6.3.2;Both the composition and organization of cytoskeletal elements in axons and dendrites become specialized early in differentiation;136
10.6.4;Cytoskeletal Structures in the Neuron Have Complementary Distributions and Functions;137
10.6.4.1;Microfilament and microtubule dynamics underlie growth cone motility and function;137
10.6.4.2;The axonal cytoskeleton may be influenced by glia;137
10.6.4.3;Levels of cytoskeletal protein expression change after injury and during regeneration;139
10.6.4.4;Alterations in the cytoskeleton are frequent hallmarks of neuropathology;139
10.6.4.5;Phosphorylation of cytoskeletal proteins is involved both in normal function and in neuropathology;141
10.6.5;Summary;141
10.6.6;References;141
10.7;7. Intracellular Trafficking;144
10.7.1;Introduction;145
10.7.2;General Mechanisms of Intracellular Membrane Trafficking in Mammalian Cells Include Both Universal and Highly Specialized Processes;145
10.7.3;Fundamentals of Membrane Trafficking are Based on a set of Common Principles;146
10.7.3.1;Most transport vesicles bud off as coated vesicles, with a unique set of proteins decorating their cytosolic surface;146
10.7.3.2;GTP-binding proteins, such as small monomeric GTPases and heterotrimeric GTPases (G proteins) facilitate membrane transport;147
10.7.3.3;Dynamins are involved in pinching off of many vesicles and membrane-bounded organelles;148
10.7.3.4;Removal of coat proteins is catalyzed by specific protein chaperones;149
10.7.3.5;SNARE proteins and rabs control recognition of specific target membranes;150
10.7.3.6;Unloading of the transport vesicle cargo to the target membrane occurs by membrane fusion;150
10.7.4;The biosynthetic Secretory Pathway Includes Synthetic, Processing, Targeting and Secretory Steps;151
10.7.4.1;Historically, endoplasmic reticulum has been classified as rough or smooth, based on the presence (RER) or absence (SER) of membraneassociated polysomes;151
10.7.4.2;Biosynthetic and secretory cargo leaving the ER is packaged in COPII-coated vesicles for delivery to the Golgi complex;152
10.7.4.3;The Golgi apparatus is a highly polarized organelle consisting of a series of flattened cisternae, usually located near the nucleus and the centrosome;154
10.7.4.4;Processing of proteins in the Golgi complex includes sorting and glycosylation of membrane proteins and secretory proteins;154
10.7.4.5;Proteins and lipids move through Golgi cisternae from the cis to the trans direction;155
10.7.4.6;Plasma membrane proteins are sorted to their final destinations at the trans-Golgi network;156
10.7.4.7;Lysosomal proteins are also sorted and targeted in the trans-Golgi network;157
10.7.4.8;Several intracellular trafficking pathways converge at lysosomes;157
10.7.4.9;Both constitutive and regulated neuroendocrine secretion pathways exist in cells of the nervous system;157
10.7.4.10;The constitutive secretory pathway is also known as the default pathway because it occurs in the absence of a triggering signal;159
10.7.4.11;Secretory cells, including neurons, possess a specialized regulated secretory pathway;159
10.7.4.12;Secretory vesicle biogenesis requires completion of a characteristic sequence of steps before vesicles are competent for secretion;159
10.7.5;The Endocytic Pathway Plays Multiple Roles in Cells of the Nervous System;160
10.7.5.1;Endocytosis for degradation of macromolecules and uptake of nutrients involves phagocytosis, pinocytosis and autophagy;160
10.7.5.2;Retrieval of membrane components in the secretory pathway through receptor-mediated endocytosis (RME) is a clathrin-coat-dependent process;162
10.7.6;Synaptic Vesicle Trafficking is a Specialized Form of Regulated Secretion and Recycling Optimized for Speed and Efficiency;164
10.7.6.1;The organization of the presynaptic terminal is one important element for optimization of secretion and recycling;164
10.7.6.2;In a simplistic model, the exocytosis step of neurotransmission takes place in at least three major different steps;164
10.7.6.3;Many years have passed since the concept of synaptic vesicle recycling was introduced in the early 1970s, but details…;167
10.7.7;Acknowledgments;169
10.7.8;References;169
10.8;8. Axonal Transport;171
10.8.1;Introduction;171
10.8.2;Neuronal Organelles in Motion;172
10.8.3;Discovery and Development of the Concept of Fast and Slow Components of Axonal Transport;172
10.8.3.1;The size and extent of many neurons presents a special set of challenges;172
10.8.3.2;Fast and slow components of axonal transport differ in both their constituents and their rates;173
10.8.3.3;Features of fast axonal transport demonstrated by biochemical and pharmacological approaches are apparent from video images;176
10.8.4;Fast Axonal Transport;176
10.8.4.1;Newly synthesized membrane and secretory proteins destined for the axon travel by fast anterograde transport;176
10.8.4.2;Passage through the golgi apparatus is obligatory for most proteins destined for fast axonal transport;177
10.8.4.3;Anterograde fast axonal transport moves synaptic vesicles, axolemmal precursors, and mitochondria down the axon;178
10.8.4.4;Retrograde transport returns trophic factors, exogenous material, and old membrane constituents to the cell body;178
10.8.4.5;Molecular sorting mechanisms ensure delivery of proteins to discrete membrane compartments;179
10.8.5;Slow Axonal Transport;180
10.8.5.1;Cytoplasmic and cytoskeletal elements move coherently at slow transport rates;180
10.8.5.2;Axonal growth and regeneration are limited by rates of slow axonal transport;180
10.8.5.3;Properties of slow axonal transport suggest molecular mechanisms;181
10.8.6;Molecular Motors: Kinesin, Dynein and Myosin;181
10.8.6.1;The characteristic biochemical properties of different molecular motors aided in their identification;182
10.8.6.2;Kinesins mediate anterograde fast axonal transport in a variety of cell types;182
10.8.6.3;Mechanisms underlying attachment of motors to transported MBOs remain elusive;183
10.8.6.4;Multiple members of the kinesin superfamily are expressed in the nervous system;183
10.8.6.5;Cytoplasmic dyneins have multiple roles in the neuron;184
10.8.6.6;Different classes of myosin are important for neuronal function;185
10.8.6.7;Matching motors to physiological functions may be difficult;185
10.8.7;AXONAL Transport and Neuropathology;186
10.8.8;Acknowledgments;187
10.8.9;References;187
10.9;9. Cell Adhesion Molecules;190
10.9.1;Overview;190
10.9.1.1;Cell adhesion molecules comprise several ‘superfamilies’;191
10.9.2;Immunoglobulin Superfamily;191
10.9.2.1;The immunoglobulin (Ig)-like domain is a typical feature of proteins belonging to the immunoglobulin superfamily;191
10.9.2.2;Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) represent a diverse group of proteins;191
10.9.2.3;IgCAMs signal to the cytoplasm;193
10.9.3;Cadherins;194
10.9.3.1;The extracellular cadherin (EC) repeat is a typical feature of cadherins;194
10.9.3.2;The type I (‘classic’) cadherins are homophilic cell adhesion molecules;194
10.9.3.3;Cadherins are involved in multiple processes in the nervous system;194
10.9.4;Integrins;195
10.9.4.1;Integrins are the major cell surface receptors responsible for cell adhesion to extracellular matrix (ECM) proteins;195
10.9.4.2;Integrins signal in an inside-out and outside-in fashion;197
10.9.4.3;Integrins regulate myelination;198
10.9.5;Cooperation and Crosstalk between Cell Adhesion Molecules;200
10.9.5.1;Various cell adhesion molecules cooperatively regulate the formation of interneuronal synapses in the CNS;200
10.9.5.2;Integrin-cadherin cross-talk regulates neurite outgrowth;202
10.9.6;Summary;203
10.9.7;References;203
10.10;10. Myelin Structure and Biochemistry;205
10.10.1;The Myelin Sheath;205
10.10.1.1;Myelin facilitates conduction;205
10.10.1.2;Myelin has a characteristic ultrastructure;206
10.10.1.2.1;Nodes of Ranvier;207
10.10.1.3;Myelin is an extension of a cell membrane;209
10.10.1.4;Myelin affects axonal structure;210
10.10.2;Characteristic Composition of Myelin;210
10.10.2.1;The composition of myelin is well characterized because it can be isolated in high yield and purity by subcellular fractionation;210
10.10.2.2;Central nervous system myelin is enriched in certain lipids;211
10.10.2.3;Peripheral and central nervous system myelin lipids are qualitatively similar;212
10.10.2.4;Central nervous system myelin contains some unique proteins;213
10.10.2.4.1;Proteolipid protein;213
10.10.2.4.2;Myelin basic proteins;214
10.10.2.4.3;2':3'-cyclic nucleotide 3'-phosphodiesterase;215
10.10.2.4.4;Myelin-associated glycoprotein (MAG) and other glycoproteins of CNS myelin;216
10.10.2.5;Peripheral myelin also contains unique proteins;217
10.10.2.5.1;P0 glycoprotein;217
10.10.2.5.2;Peripheral myelin protein-22;217
10.10.2.5.3;P2 protein;218
10.10.2.6;Some classically defined myelin proteins are common to both CNS and PNS myelin;218
10.10.2.6.1;Myelin basic protein;218
10.10.2.6.2;Myelin-associated glycoprotein;218
10.10.2.7;Myelin sheaths contain other proteins, some of which have only recently been established as myelin related;219
10.10.2.7.1;Tetraspan proteins;219
10.10.2.7.2;Nodal, paranodal, and juxtaparanodal proteins;220
10.10.2.7.3;Enzymes associated with myelin;220
10.10.2.7.4;Neurotransmitter receptors associated with myelin;222
10.10.2.7.5;Other myelin-related proteins;222
10.10.3;Acknowledgments;222
10.10.4;References;222
10.11;11. Energy Metabolism of the Brain;225
10.11.1;Introduction;226
10.11.1.1;Processes related to signaling require a larger proportion of energy than do ‘basic’ cellular functions;226
10.11.1.2;Function-derived signals arising from metabolism are used for brain imaging;227
10.11.1.3;Major cell types and their subcellular structures have different energetic requirements and metabolic capabilities;228
10.11.2;Substrates for Cerebral Energy Metabolism;228
10.11.2.1;Energy-yielding substrates enter the brain from the blood through the blood–brain barrier;228
10.11.2.2;Endothelial cells of the blood–brain barrier and brain cells have specific transporters for the uptake of glucose and monocarboxylic acids;228
10.11.2.3;Blood–brain barrier transport can be altered under pathological conditions;229
10.11.3;Age and Development Influence Cerebral Energy Metabolism;229
10.11.3.1;The transporters and pathways of metabolism change during development;229
10.11.3.2;Cerebral metabolic rate increases during early development;230
10.11.3.3;Cerebral metabolic rate declines from developmental levels and plateaus after maturation;230
10.11.4;Fueling Brain: Supply–Demand Relationships and Cerebral Metabolic Rate;230
10.11.4.1;Both excitatory and inhibitory neuronal signals utilize energy derived from metabolism;230
10.11.4.2;Continuous cerebral circulation is required to sustain brain function;231
10.11.4.3;Glucose is the main obligatory substrate for energy metabolism in adult brain;231
10.11.5;Metabolism in the Brain is Highly Compartmentalized;232
10.11.5.1;Glucose has numerous metabolic fates in brain;232
10.11.6;Glycolysis: Conversion of Glucose to Pyruvate;232
10.11.6.1;Regulation of brain hexokinase;232
10.11.6.2;Phosphofructokinase is the major regulator of brain glycolysis;233
10.11.6.3;Glycolysis produces ATP, pyruvate for mitochondrial metabolism, and precursors for amino acids and complex carbohydrates;233
10.11.7;Glycogen is Actively Synthesized and Degraded in Astrocytes;234
10.11.7.1;The steady-state concentration of glycogen is regulated by coordination of separate degradative and synthetic enzymatic processes;235
10.11.8;The Pentose Phosphate Shunt has Essential Roles in Brain;235
10.11.9;The Malate–Aspartate Shuttle has a key Role in Brain Metabolism;235
10.11.9.1;The malate–aspartate shuttle is the most important pathway for transferring reducing equivalents from the cytosol to the…;235
10.11.9.2;The malate–aspartate shuttle has a role in linking metabolic pathways in brain;236
10.11.10;There is Active Metabolism of Lactate in Brain;236
10.11.10.1;Lactate–pyruvate interconversion;236
10.11.10.2;Lactate is formed in brain under many conditions;236
10.11.10.3;Compartmentation of the pyruvate–lactate pool is unexpectedly complex;239
10.11.10.4;Lactate can serve as fuel for brain cells under various conditions;239
10.11.10.5;The astrocyte–neuron lactate shuttle is controversial;240
10.11.11;Major Functions of the Tricarboxylic Acid (TCA) Cycle: Pyruvate Oxidation to CO2, NADH/FADH2 Formation for ATP Generation…;240
10.11.11.1;The TCA (citric acid) cycle is multifunctional;240
10.11.11.2;The pyruvate dehydrogenase complex plays a key role in regulating oxidation of glucose;242
10.11.11.3;TCA cycle rate;242
10.11.11.4;Malate dehydrogenase is one of several enzymes in the TCA cycle present in both the cytoplasm and mitochondria;242
10.11.11.5;The electron transport chain produces ATP;242
10.11.11.6;ATP production in brain is highly regulated;242
10.11.11.7;Phosphocreatine has a role in maintaining ATP levels in brain;243
10.11.11.8;Pyruvate carboxylation in astrocytes is the major anaplerotic pathway in brain;243
10.11.11.9;Citrate is a multifunctional compound predominantly synthesized and released by astrocytes;243
10.11.11.10;Acetyl-coenzyme A formed from glucose is the precursor for acetylcholine in neurons;243
10.11.12;Mitochondrial Heterogeneity: Differential Distribution of Many TCA Cycle Enzymes and Components of Oxidative Phosphorylation…;244
10.11.12.1;Mitochondria are distributed with varying densities throughout the central nervous system, with the more vascular parts…;244
10.11.12.2;Mitochondrial heterogeneity leads to multiple simultaneous TCA cycles in astrocytes and neurons;244
10.11.12.3;Partial TCA cycles can provide energy in brain;244
10.11.12.4;Other substrates (e.g., glutamate, glutamine, lactate, fatty acids, and ketone bodies) can provide energy for brain cells;244
10.11.13;Glutamate–Glutamine Metabolism is Linked to Energy Metabolism;245
10.11.13.1;Transporters are required to carry glutamate and other amino acids across the mitochondrial membrane;245
10.11.13.2;Metabolism of both glutamate and glutamine is linked to TCA cycle activity;245
10.11.13.3;Glutamate participates in a number of metabolic pathways, and metabolism of glutamate and glutamine is compartmentalized;245
10.11.13.3.1;The glutamate–glutamine cycle;246
10.11.13.4;A specialized glutamate–glutamine cycle operates in Gabaergic neurons and surrounding astrocytes;247
10.11.13.5;Several shuttles act to transfer nitrogen in brain;247
10.11.14;Metabolic Studies in Brain: Imaging and Spectroscopy;247
10.11.14.1;Global assays of whole brain;247
10.11.14.2;Local rates of glucose and oxygen utilization, functional brain imaging, redox state, and metabolic pathway analysis;247
10.11.14.3;Carbon-13 nuclear magnetic resonance spectroscopy (NMR or MRS) for studying brain metabolism;249
10.11.14.4;Cultured neurons and astrocytes are useful for studying subcellular compartmentation and identifying pathways of metabolism;250
10.11.14.5;Metabolic assays in brain slices, axons, synaptosomes and isolated mitochondria;251
10.11.14.6;Concentrations of compounds in brain and regulation of metabolism in the intact brain;251
10.11.15;Relation of Energy Metabolism to Pathological Conditions in the Brain;251
10.11.16;Acknowledgments;251
10.11.17;References;251
11;II. INTERCELLULAR SIGNALING;258
11.1;12. Synaptic Transmission and Cellular Signaling: An Overview;260
11.1.1;Synaptic Transmission;260
11.1.1.1;Chemical transmission between nerve cells involves multiple steps;260
11.1.1.2;Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells;262
11.1.1.3;A variety of methods have been developed to study exocytosis;263
11.1.1.4;The neuromuscular junction is a well-defined structure that mediates the release and postsynaptic effects of acetylcholine;263
11.1.1.5;Quantal analysis defines the mechanism of release as exocytosis;264
11.1.1.6;Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis;264
11.1.1.7;Presynaptic events during synaptic transmission are rapid, dynamic and interconnected;266
11.1.1.8;Because fast synaptic transmission involves recycling vesicles, the neurotransmitter must be replenished locally;270
11.1.1.9;Discrete steps in the regulated secretory pathway can be defined in neuroendocrine cells;270
11.1.2;Cellular Signaling Mechanisms;270
11.1.2.1;Background;270
11.1.2.2;Three phases of receptor-mediated signaling can be identified;271
11.1.2.3;Several major molecular mechanisms that link agonist occupancy of cell-surface receptors to functional responses have been identified;271
11.1.2.3.1;First group;271
11.1.2.3.2;Second group;273
11.1.2.3.3;Third group;273
11.1.2.3.4;Fourth group;273
11.1.2.4;Cross-talk can occur between intracellular signaling pathways;274
11.1.2.5;Signaling molecules can activate gene transcription;274
11.1.2.6;Nitric oxide acts as an intercellular signaling molecule in the central nervous system;274
11.1.2.7;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
11.2.2.1;Acetylcholine formation is catalyzed by choline acetyltransferase;285
11.2.2.2;Choline is accumulated into synaptic terminals via a specific high-affinity transporter;285
11.2.2.3;ACh is packaged into vesicles by a specific transporter and is released from neurons in a Ca2+-dependent manner;286
11.2.2.4;Cholinergic neurons are widely distributed within the CNS;287
11.2.3;Enzymatic Breakdown of Acetylcholine;287
11.2.3.1;Acetylcholinesterase and the removal of ACh;287
11.2.3.2;Molecular forms of AChE;287
11.2.3.3;AChE is encoded by a single gene that is subject to alternative splicing;288
11.2.3.4;AChE catalysis: mechanism of a nearly perfect enzyme;288
11.2.3.5;The active site is at the bottom of a narrow gorge in the AChE protein;289
11.2.3.6;Inhibitors of AChE have toxicological, agrochemical and clinical significance;290
11.2.3.7;Does AChE have other functions?;291
11.2.4;Nicotinic Cholinergic Receptors;291
11.2.4.1;The nicotinic receptor was the first receptor to be characterized biochemically;291
11.2.4.2;nAChRs are pentameric ligand-gated ion channels;292
11.2.4.3;Agonists bind at the interface between adjacent subunits;293
11.2.4.4;The nAChR is the prototypical member of the cys-loop family of ligand-gated ion channel receptors;294
11.2.4.5;The nAChR ion channel;294
11.2.4.6;The prolonged presence of agonist leads to desensitization;294
11.2.4.7;Neuronal nAChRs form a family of related receptors;294
11.2.4.8;The permutations of subunits forming nAChRs create more diversity;296
11.2.4.9;Neuronal nAChRs modulate brain function;296
11.2.4.10;Transgenic mice help to reveal the physiological roles and clinical implications of nAChRs;296
11.2.4.11;Neuronal nAChRs are also present in non-neuronal cells;297
11.2.4.12;nAChRs and disease;297
11.2.4.13;nAChRs as therapeutic targets;298
11.2.5;Muscarinic Cholinergic Receptors;299
11.2.5.1;Some effects of ACh can be mimicked by the alkaloid muscarine;299
11.2.5.2;Muscarinic cholinergic responses are mediated by G-protein–coupled receptors;299
11.2.5.3;Pharmacological studies were the first to indicate the presence of multiple mAChR subtypes;299
11.2.5.4;Molecular cloning of the mAChR reveals five subtypes;300
11.2.5.5;Muscarinic receptor subtypes couple to distinct G-proteins and activate different effector mechanisms;301
11.2.5.6;Muscarinic receptor subtypes are not uniformly distributed throughout the CNS and are present at different subcellular locations;302
11.2.5.7;Muscarinic receptors in the CNS have been implicated in a number of neuropsychiatric disorders;302
11.2.5.8;Transgenic mice permit an assessment of the physiological roles of individual subtypes in vivo;302
11.2.5.9;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
11.3.1.1;Catecholamines belong to the group of transmitters called monoamines;308
11.3.1.2;Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis;309
11.3.1.3;Aromatic amino acid decarboxylase (AAAD), also called DOPA decarboxylase, catalyzes the conversion of L-DOPA to dopamine;310
11.3.1.4;In noradrenergic and adrenergic neurons, dopamine is further converted to norepinephrine by Dopamine-ß-hydroxylase (DBH);311
11.3.1.5;In select neurons and adrenal medulla, norepinephrine is metabolized to epinephrine by phenylethanolamine-n-methyltransferase (PNMT);313
11.3.1.6;Catecholamines are stored in small, clear synaptic vesicles or large, dense-core granules;313
11.3.1.7;Catecholamines are released from synaptic vesicles and the vesicles recycle;313
11.3.1.8;The physiological actions of catecholamines are terminated by reuptake into the neuron, catabolism and diffusion;313
11.3.1.9;Diffusion also plays an important role in the inactivation of catecholamines;315
11.3.1.10;Catecholamines are primarily metabolized by monoamine oxidase and catechol-o-methyltransferase;315
11.3.1.10.1;Monoamine oxidase (MAO);315
11.3.1.10.2;Catechol-O-methyltransferase (COMT);316
11.3.1.10.3;Dopamine metabolites;317
11.3.1.10.4;Norepinephrine metabolism;317
11.3.2;Neuroanatomy;317
11.3.2.1;Catecholamines elicit their effects by binding to cell-surface receptors;318
11.3.3;Adrenergic Receptors;320
11.3.3.1;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
11.4.1.1;The indolealkylamine 5-hydroxytryptamine (5-HT; serotonin) was initially identified because of its effects on smooth muscle;326
11.4.1.2;Understanding the neuroanatomical organization of serotonergic neurons provides insight into the functions of this neurotransmitter…;326
11.4.1.3;The amino acid L-tryptophan serves as the precursor for the synthesis of 5-HT;329
11.4.1.4;The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter;331
11.4.1.5;As with other biogenic amine transmitters, 5-HT is stored primarily in vesicles and is released by an exocytotic mechanism;331
11.4.1.6;The activity of 5-HT in the synapse is terminated primarily by its reuptake into serotonergic terminals;333
11.4.1.7;Acute and chronic regulation of SERT function provides mechanisms for altering synaptic 5-HT concentrations and neurotransmission;334
11.4.1.8;The primary catabolic pathway for 5-HT is oxidative deamination by the enzyme monoamine oxidase;335
11.4.1.9;In addition to classical synaptic transmission, 5-HT may relay information by volume transmission or paracrine neurotransmission;336
11.4.1.10;5-HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state…;336
11.4.1.11;5-HT modulates neuroendocrine function;337
11.4.1.12;5-HT modulates circadian rhythmicity;337
11.4.1.13;5-HT modulates feeding behavior and food intake;337
11.4.2;Serotonin Receptors;338
11.4.2.1;Pharmacological and physiological studies have contributed to the definition of the many receptor subtypes for serotonin;338
11.4.2.2;The application of techniques used in molecular biology to the study of 5-HT receptors led to the rapid discovery of addition…;339
11.4.2.3;The 5-HT1 receptor family is composed of the 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-HT1F receptors;339
11.4.2.3.1;The 5-HT1A receptor;339
11.4.2.3.2;The 5-HT1B and 5-HT1D receptor subtypes;341
11.4.2.3.3;The 5-ht1E receptor;342
11.4.2.3.4;The 5-HT1F receptor;342
11.4.2.4;The 5-HT2 receptor family is composed of the 5-HT2A, 5-HT2B and 5HT2C receptors;342
11.4.2.4.1;5-HT2A receptors;342
11.4.2.4.2;The 5-HT2B receptor;343
11.4.2.4.3;The 5-HT2C receptor;343
11.4.2.5;Unlike the other subtypes of receptor for 5-HT, the 5-HT3 receptor is a ligand-gated ion channel;343
11.4.2.5.1;The 5-HT3 receptor;343
11.4.2.6;The 5-HT4, 5-HT6 and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase;344
11.4.2.6.1;The 5-HT4 receptor;344
11.4.2.6.2;The 5-HT6 receptor;345
11.4.2.6.3;The 5-HT7 receptor;345
11.4.2.7;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
11.5.2.1;Histamine is a mediator of several physiological and pathological processes within and outside of the nervous system;349
11.5.2.2;The chemical structure of histamine has similarities to the structures of other biogenic amines, but important differences also exist;349
11.5.3;Histaminergic Cells of the Central Nervous System: Anatomy and Morphology;349
11.5.3.1;The brain stores and releases histamine from more than one type of cell;349
11.5.3.2;Several functions for brain and dural mast cells are investigated;349
11.5.3.3;Histaminergic fibers originate from the tuberomamillary (TM) region of the posterior hypothalamus;349
11.5.3.4;Histaminergic neurons have morphological and membrane properties that are similar to those of neurons storing other biogenic amines;350
11.5.3.5;Histaminergic fibers project widely to most regions of the central nervous system;350
11.5.4;Dynamics of Histamine in the Brain;352
11.5.4.1;Specific enzymes control histamine synthesis and breakdown;352
11.5.4.2;Several forms of histidine decarboxylase (HDC) may derive from a single gene;353
11.5.4.3;Histamine synthesis in the brain is controlled by the availability of l-histidine and the activity of HDC;353
11.5.4.4;Histamine is stored within and released from neurons;353
11.5.4.5;In the vertebrate brain, histamine metabolism occurs predominantly by methylation;353
11.5.4.6;Neuronal histamine can be methylated outside of histaminergic nerve terminals;353
11.5.4.7;A polymorphism in human HMT (Thr105Ile) may be an important regulatory factor in some human disorders;354
11.5.4.8;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
11.5.5.1;Histamine acts on four G-protein–coupled receptors (GPCRs), three of which are clearly important in the brain;354
11.5.5.2;H1 receptors are intronless GPCRs linked to Gq and calcium mobilization;354
11.5.5.2.1;H1-linked intracellular messengers;355
11.5.5.3;H2 receptors are intronless GPCRs linked to Gs and cyclic AMP synthesis;356
11.5.5.3.1;H2-linked intracellular messengers;356
11.5.5.4;H3 receptors are a family of GPCRs produced by gene splicing and linked to Gi/o;356
11.5.5.4.1;H3 receptor gene splicing;358
11.5.5.4.2;H3-linked intracellular messengers;358
11.5.5.4.3;Constitutive H3 receptor activity;359
11.5.5.5;H4 receptors are very similar to H3 receptors in gene structure and signal transduction, but show limited expression in the brain;359
11.5.5.5.1;H4-linked intracellular messengers;360
11.5.5.6;Histamine can modify ionotropic transmission;360
11.5.6;Histamine Actions on the Nervous System;360
11.5.6.1;Histamine in the brain may act as both a neuromodulator and a classical transmitter;360
11.5.6.2;Histaminergic neurons are mutually connected with other neurotransmitter systems;360
11.5.6.3;Histamine functions in the nervous system;361
11.5.6.4;Histamine may contribute to nervous system diseases or disorders;362
11.5.7;Significance of Brain Histamine for Drug Action;362
11.5.7.1;Many clinically available drugs that modify sleep–wake cycles and appetite act through the histaminergic system;362
11.5.7.2;Drugs that modify pain perception act in part through the histaminergic system;362
11.5.7.3;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 Blood–Brain Barrier;368
11.6.3;Glutamine is an Important Immediate Precursor for Glutamate: The Glutamine Cycle;369
11.6.3.1;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
11.6.4.1;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 Hippocampus 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
11.6.9.1;Seven functional families of ionotropic glutamate receptor subunits can be defined by structural homologies;373
11.6.9.2;AMPA and kainate receptors are both blocked by quinoxalinediones but have different desensitization pharmacologies;375
11.6.9.3;N-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites;375
11.6.9.4;The transmembrane topology of glutamate receptors differs from that of nicotinic receptors;379
11.6.9.5;Structure of the agonist-binding site has been analyzed;379
11.6.9.6;Genetic regulation via splice variants and RNA editing further increases receptor heterogeneity: the flip/flop versions…;379
11.6.9.7;The permeation pathways of all ionotropic glutamate receptors are similar, but vive la difference;381
11.6.10;Glutamate Produces Excitatory Postsynaptic Potentials;381
11.6.10.1;Genetic knockouts provide clues to ionotropic receptor functions;383
11.6.11;Metabotropic Glutamate Receptors Modulate Synaptic Transmission;383
11.6.11.1;Eight metabotropic glutamate receptors (mGlu receptors) have been identified that embody three functional classes;383
11.6.11.2;mGlu receptors are linked to diverse cytoplasmic signaling enzymes;383
11.6.11.3;Postsynaptic mGlu receptor activation modulates ion channel activity;383
11.6.11.4;Presynaptic mGlu receptor activation can lead to presynaptic inhibition;384
11.6.11.5;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
11.6.13.1;A major scaffolding protein of the PSD is PSD95;385
11.6.13.2;Small GTP-binding proteins (GTPases) mediate changes in gene expression upon NMDA 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
11.6.17.1;Glutamate and its analogs can be neurotoxins and cause excitotoxicity;388
11.6.17.2;Some dietary neurotoxins may cause excessive glutamate receptor activation and cell death;388
11.6.17.3;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
11.7.2.1;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
11.7.3.1;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
11.7.4.1;GABAB receptors are coupled to G proteins and a variety of effectors;394
11.7.4.2;GABAB receptors are heterodimers;394
11.7.4.3;GABAA receptors are chloride channels and members of a superfamily of ligand-gated ion channel receptors;395
11.7.4.4;A family of pentameric GABAA-receptor protein subtypes exists; these vary in their localization, and in virtually every pro ...;395
11.7.4.5;The GABAA receptor is the major molecular target for the action of many drugs in the brain;397
11.7.4.6;Neurosteroids, which may be physiological endogenous modulators of brain activity, enhance GABAA receptor function;399
11.7.4.7;The three-dimensional structures of ligand-gated ion channel receptors are being modeled successfully;399
11.7.4.8;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
11.8.2.1;Extracellular nucleotides are regulated by ectoenzymes;404
11.8.2.2;There are several sources of extracellular adenosine;404
11.8.3;Purinergic Receptors;407
11.8.3.1;There are four adenosine receptor subtypes;407
11.8.3.2;Adenosine A1 receptors (A1R);408
11.8.3.3;A2A adenosine receptors are highly expressed in the basal ganglia;408
11.8.3.4;A2B adenosine receptors regulate vascular permeability;409
11.8.3.5;A3 adenosine receptors are few in number in the central nervous system;409
11.8.3.6;P2 receptors are subdivided into ionotropic P2X receptors and metabotropic P2Y receptors;409
11.8.4;Effects of Purines in the Nervous System;409
11.8.4.1;ATP-adenosine is an important glial signal;409
11.8.4.2;Myelination and importance of the axonal release of ATP;410
11.8.4.3;Astrocyte-mediated, adenosine-dependent heterosynaptic depression;410
11.8.4.4;Behavioral roles for glial-derived ATP and adenosine: respiration and sleep;410
11.8.4.5;pH-dependent release of purines from astrocytes controls breathing;411
11.8.4.6;Microglia and their response to injury;411
11.8.4.7;Adenosine and the effects of alcohol;412
11.8.5;Disorders of the Nervous System—Purines 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: Parkinson’s 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
11.9.1.1;Many neuropeptides were originally identified as pituitary or gastrointestinal hormones;415
11.9.1.2;Peptides can be grouped by structural and functional similarity;416
11.9.1.3;The function of peptides as first messengers is evolutionarily very old;417
11.9.1.4;Various techniques are used to identify additional neuropeptides;417
11.9.1.5;The neuropeptides exhibit a few key differences from the classical neurotransmitters;417
11.9.1.6;Neuropeptides are often found in neurons with conventional neurotransmitters;418
11.9.1.7;The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters;419
11.9.1.8;Many of the enzymes involved in peptide biogenesis have been identified;419
11.9.1.9;Neuropeptides are packaged into large, dense-core vesicles;424
11.9.1.10;Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modification;424
11.9.2;Neuropeptide Receptors;425
11.9.2.1;Most neuropeptide receptors are seven-transmembrane-domain, G-protein–coupled receptors;425
11.9.2.2;Neuropeptide receptors are not confined to synaptic regions;426
11.9.2.3;Expressions of peptide receptors and the corresponding peptides are not well matched;427
11.9.2.4;The amiloride-sensitive FMRF-amide-gated sodium ion channel is among the few peptide-gated ion channels identified;427
11.9.2.5;Neuropeptide receptors are becoming molecular targets for therapeutic drugs;427
11.9.3;Neuropeptide Functions and Regulation;427
11.9.3.1;The study of peptidergic neurons requires a number of special tools;427
11.9.3.2;Peptides play a role in the plurichemical coding of neuronal signals;428
11.9.3.3;Neuropeptides make a unique contribution to signaling;428
11.9.3.4;Regulation of neuropeptide expression is exerted at several levels;428
11.9.4;Peptidergic Systems in Disease;429
11.9.4.1;Diabetes insipidus occurs with a loss of vasopressin production in the Brattleboro rat model;429
11.9.4.2;Mutations and knockouts of peptide-processing enzyme genes cause a myriad of physiological problems;429
11.9.4.3;Neuropeptides play key roles in appetite regulation and obesity;430
11.9.4.4;Enkephalin knockout mice reach adulthood and are healthy;430
11.9.4.5;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
12.1.1.1;The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions;436
12.1.1.2;Multiple forms of heterotrimeric G protein exist in the nervous system;437
12.1.1.3;Each G protein is a heterotrimer composed of single a, ß and . subunits;437
12.1.1.4;The functional activity of G proteins involves their dissociation and reassociation in response to extracellular signals;437
12.1.1.5;G proteins couple some neurotransmitter receptors directly to ion channels;437
12.1.1.6;G proteins regulate intracellular concentrations of second messengers;439
12.1.1.7;G proteins have been implicated in membrane trafficking;440
12.1.1.8;G protein ß. subunits subserve numerous functions in the cell;440
12.1.1.9;The functioning of heterotrimeric G proteins is modulated by other proteins;441
12.1.1.10;G proteins are modified covalently by the addition of long-chain fatty acids;443
12.1.1.11;The functioning of G proteins may be influenced by phosphorylation;443
12.1.2;Small G Proteins;443
12.1.2.1;The best-characterized small G protein is the Ras family, a series of related proteins of 21 kDa;443
12.1.2.2;Rab is a family of small G proteins involved in membrane vesicle trafficking;444
12.1.3;Other Features of G Proteins;444
12.1.3.1;G proteins can be modified by ADP-ribosylation catalyzed by certain bacterial toxins;444
12.1.3.2;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
12.2.2.1;Biochemistry of cAMP production;448
12.2.2.2;Adenylyl cyclase isozymes: expression and regulation;450
12.2.2.2.1;Group 1 adenylyl cyclases;450
12.2.2.2.1.1;Adenylyl Cyclase 1;450
12.2.2.2.1.2;Adenylyl Cyclases 3 and 8;451
12.2.2.2.2;Group 2 adenylyl cyclases;451
12.2.2.2.2.1;Adenylyl Cyclase 2;451
12.2.2.2.2.2;Adenylyl Cyclase 4 and 7;451
12.2.2.2.3;Group 3 adenylyl cyclases;452
12.2.2.2.3.1;Adenylyl Cyclase 5;452
12.2.2.2.3.2;Adenylyl Cyclase 6;452
12.2.2.2.4;Group 4 adenylyl cyclase;452
12.2.2.2.5;Soluble adenylyl cyclase;452
12.2.2.3;Models for cellular regulation of the different types of adenylyl cyclase;452
12.2.2.4;Long-term regulation of adenylyl cyclases;454
12.2.2.5;Molecular targets of c454
12.2.2.5.1;Protein kinase A;454
12.2.2.5.2;Cyclic nucleotide-gated channels;454
12.2.2.5.3;Epac;455
12.2.2.5.4;Functions of cAMP signaling in the brain;455
12.2.2.5.5;Synaptic plasticity, learning, and memory;455
12.2.2.5.6;Pain;455
12.2.2.5.7;Dopamine signaling in the striatum;455
12.2.2.5.8;Neurodegeneration;455
12.2.2.5.9;Drugs of abuse;455
12.2.2.5.10;Olfaction;455
12.2.3;Guanylyl Cyclases;455
12.2.3.1;Membrane-bound guanylyl cyclase;456
12.2.3.1.1;GC-A, -B and -C are receptors for natriuretic peptides;457
12.2.3.1.2;GC-D and GC-G are implicated in olfaction;457
12.2.3.1.3;GC-E and GC-F are involved in photoreceptor signal transduction;457
12.2.3.2;Soluble guanylyl cyclases;457
12.2.3.3;sGC is regulated by nitric oxide (NO);458
12.2.3.4;Molecular effectors of cGMP signaling;458
12.2.3.4.1;Protein kinase G;458
12.2.3.4.2;cGMP-gated ion channels;458
12.2.3.4.3;Phosphodiesterases;458
12.2.3.4.4;Functions of cGMP signaling in the brain;458
12.2.3.4.5;Synaptic plasticity, learning, and memory;459
12.2.3.4.6;Cognition and mood;459
12.2.3.4.7;Pain;459
12.2.4;Phosphodiesterases;459
12.2.4.1;Structure of phosphodiesterases;459
12.2.4.2;Families of phosphodiesterases;459
12.2.4.2.1;Ca2+/calmodulin-stimulated PDEs (PDE1);459
12.2.4.2.2;cGMP-regulated PDEs (PDE2, PDE3, and PDE11);460
12.2.4.2.3;G protein–activated phosphodiesterase in retinal phototransduction: PDE6;461
12.2.4.2.4;PDEs regulated primarily by phosphorylation: PDE4, 5 and 10;462
12.2.4.2.5;PDE7, 8 and 9;463
12.2.4.3;Phosphodiesterases as 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
12.3.2.1;The three quantitatively major phosphoinositides are structurally and metabolically related;468
12.3.2.2;The quantitatively minor 3'-phosphoinositides are synthesized by phosphatidylinositol 3-kinase;469
12.3.2.3;Phosphoinositides are dephosphorylated by phosphatases;470
12.3.2.4;Phosphoinositides are cleaved by a family of phosphoinositide-specific phospholipase C (PLC) isozymes;471
12.3.3;The Inositol Phosphates;473
12.3.3.1;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
12.3.3.2;The metabolism of inositol phosphates leads to regeneration of free inositol;474
12.3.3.3;Highly phosphorylated forms of myo-inositol are present in cells;474
12.3.4;Diacylglycerol;474
12.3.4.1;Protein kinase C is activated by the second messenger diacylglycerol;474
12.3.5;Phosphoinositides and Cell Regulation;476
12.3.5.1;Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers;476
12.3.5.1.1;Membrane trafficking;476
12.3.5.1.2;Cell growth and cell survival;477
12.3.5.1.3;Regulation of ion channel activity;477
12.3.6;References;478
12.4;24. Calcium;480
12.4.1;The Calcium Signal in Context;480
12.4.2;Calcium Measurement;481
12.4.2.1;Much of our understanding of the essential role of Ca2+ in cellular physiology has been indirect;481
12.4.2.2;Current optical methods to measure calcium use chemical or protein-based fluorescent indicators;481
12.4.2.2.1;The optical monitoring of [Ca2+] relies on indicators whose fluorescence changes upon binding to calcium;481
12.4.2.2.2;Increased resolution can be accomplished optically or by targeting indicator proteins;482
12.4.3;Calcium Homeostasis at the Plasma Membrane;482
12.4.3.1;The balance between calcium efflux and influx at the plasma membrane determines [Ca2+];482
12.4.3.2;Efflux pathways — pumps and transporters;483
12.4.3.3;Influx pathways — Ca enters the cell through four major routes;483
12.4.4;Cellular Organelles and Calcium Pools;483
12.4.4.1;The endoplasmic reticulum is the primary intracellular calcium store;484
12.4.4.2;The ER has pumps, storage buffersand Ca2+ release channels;484
12.4.4.2.1;Activation of different ER signaling pathways elicit different responses;484
12.4.4.2.2;Store-operated Ca2+ entry: The ER signals when empty to open channels in the plasma membrane;485
12.4.4.3;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
12.4.6.1;Electrically silent astrocytes use Ca2+ as a signaling molecule;486
12.4.6.2;The tripartite synapse: gliotransmitters and modulation of transmission at the synapse;487
12.4.6.3;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
12.5.1.1;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
12.5.2.1;Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation;495
12.5.2.2;Second messenger–dependent protein Ser/Thr kinases;498
12.5.2.2.1;cAMP-dependent protein kinase;498
12.5.2.2.2;cGMP-dependent protein kinase;498
12.5.2.2.3;Protein kinase C;498
12.5.2.2.4;Calcium2+/calmodulin-dependent kinases;500
12.5.2.3;Second messenger–independent protein Ser/Thr kinases;501
12.5.2.4;The MAPK cascade is a classical example of second messenger–independent protein Ser/Thr kinase signaling;501
12.5.2.4.1;Extracellular signal-regulated protein kinases (ERKs);502
12.5.2.4.2;p38 MAPKs;502
12.5.2.4.3;c-Jun NH2-terminal kinases;502
12.5.2.5;The brain contains many other types of second messenger–independent protein Ser/Thr kinases;503
12.5.2.5.1;Cyclin-dependent kinase 5 (CDK5);503
12.5.2.5.2;Glycogen-synthase kinase-3 (GSK3);503
12.5.2.5.3;Casein kinase 1 (CK1);503
12.5.2.5.4;Protein phosphatase 1 (PP1);504
12.5.2.5.5;Protein phosphatase 2A (PP2A);505
12.5.2.5.6;Protein phosphatase 2B (PP2B);505
12.5.2.5.7;Protein phosphatase 2C (PP2C);506
12.5.2.5.8;Dual-specificity phosphatases (DUSPs);506
12.5.3;Protein Ser/Thr Phosphatases;504
12.5.3.1;Common strategies used for the evaluation of neuronal functions of protein kinases and phosphatases;506
12.5.4;Neuronal Phosphoproteins;507
12.5.4.1;Phosphorylation can influence protein function in various ways;507
12.5.4.1.1;Proteins are often subject to complex phosphoregulation;508
12.5.4.2;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
12.5.5.1;Presynaptic mechanisms regulated by protein phosphorylation;510
12.5.5.2;Postsynaptic mechanisms regulated by protein phosphorylation;512
12.5.5.3;Extrasynaptic mechanisms regulated by protein phosphorylation;514
12.5.6;Protein Phosphorylation in Human Neuronal Disorders;514
12.5.6.1;Genetic neuronal disorders due to mutations in genes of protein kinases and phosphatases;514
12.5.6.2;Protein phosphorylation in pathophysiological processes in diseases of the nervous system;515
12.5.6.2.1;Protein phosphorylation and AD;515
12.5.7;Acknowledgments;516
12.5.8;References;516
12.6;26. Tyrosine Phosphorylation;518
12.6.1;Tyrosine Phosphorylation in the Nervous System;518
12.6.2;Protein Tyrosine Kinases;519
12.6.2.1;Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper…;519
12.6.2.2;Receptor protein tyrosine kinases consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domain;523
12.6.2.2.1;RPTK Activation;525
12.6.2.2.2;RPTK Inactivation;525
12.6.2.2.3;Tyrosine Phosphorylation of RPTKs;526
12.6.3;Protein Tyrosine Phosphatases;526
12.6.3.1;Protein tyrosine phosphatases are structurally different from serine–threonine phosphatases and contain a cysteine residue…;528
12.6.3.2;Nonreceptor tyrosine phosphatases are cytoplasmic and have regulatory sequences flanking the catalytic domain;529
12.6.3.3;Receptor protein tyrosine phosphatases consist of an extracellular domain, a transmembrane domain and one or two intracellular…;530
12.6.3.4;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
12.6.4.1;Tyrosine phosphorylation is involved in every stage of neuronal development;530
12.6.4.2;Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse;534
12.6.4.3;Tyrosine phosphorylation contributes to the formation of synapses in the central nervous system;534
12.6.4.3.1;Acetylcholine Receptors;535
12.6.4.3.2;N-Methyl-d-Aspartate Receptors;535
12.6.4.3.3;GABA Receptors;536
12.6.4.3.4;Voltage-Gated Ion Channels;536
12.6.5;References;536
12.7;27. Transcription Factors in the Central Nervous System;539
12.7.1;The Transcriptional Process;539
12.7.1.1;Co-regulators of transcription—modulation of chromatin structure;541
12.7.1.2;Histone acetylation;541
12.7.1.3;Histone and DNA methylation;542
12.7.2;Regulation of Transcription by Transcription Factors;543
12.7.2.1;Technology that has hastened the study of transcription;543
12.7.2.2;NextGen sequencing to assess the cellular transcriptome;545
12.7.3;Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors;546
12.7.3.1;Corticosteroid receptors regulate transcription in the nervous system;547
12.7.3.2;The mechanisms of corticosteroid receptor regulation of transcription have been elucidated;547
12.7.4;camp Regulation of Transcription;549
12.7.4.1;The cAMP response element–binding protein is a member of a family containing interacting proteins;550
12.7.4.2;The function of the cAMP response element–binding protein has been modeled in transgenic organisms;550
12.7.5;The Role of Transcription Factors in Cellular Phenotype;552
12.7.5.1;Transcription factors navigate the roadmap of cellular maturation;552
12.7.5.2;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
13.1.2.1;The CNS arises from the neural tube;559
13.1.2.2;The major divisions of the CNS are identifiable early in development;559
13.1.3;Spatial Regionalization;559
13.1.3.1;A dorsoventral pattern arises with signals from adjacent non-neuronal cells;559
13.1.3.2;The rostrocaudal axis is specified by homeobox-containing genes;560
13.1.3.3;Embryonic signaling centers organize large regions of the brain;563
13.1.4;Neurogenesis and Gliogenesis;564
13.1.4.1;Neurons have a birthdate;564
13.1.4.2;Reelin and notch signaling contribute to cortical layer organization;564
13.1.4.3;Neuronal specification involves proneural and neurogenic gene gunctions;565
13.1.5;PNS Development and Target Interactions;566
13.1.5.1;The neural crest gives rise to PNS derivatives by induction;566
13.1.6;Axon Guidance Contributes to Correct Connections;567
13.1.6.1;Naturally occurring cell death eliminates cells and synapses;567
13.1.7;Synapse Formation;568
13.1.7.1;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
13.2.2.1;Nerve growth factor;572
13.2.2.2;Brain-derived neurotrophic factor;573
13.2.2.3;Neurotrophin 3;575
13.2.2.4;Neurotrophin 4;575
13.2.3;Regulation of Neurotrophin Expression;576
13.2.4;Proneurotrophins;576
13.2.5;Neurotrophin Receptors;576
13.2.5.1;Trk receptors;577
13.2.5.2;The p75 neurotrophin receptor (p75NTR);577
13.2.6;Glial Cell line–Derived 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
13.3.2.1;Embryonic stem (ES) cells are derived from the inner cell mass of embryos;584
13.3.2.2;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
13.3.3.1;Neural stem cells (NSCs);585
13.3.3.2;Radial glia are stem cells;585
13.3.3.3;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
13.3.4.1;Stem cell markers in the nervous system;586
13.3.4.2;The neurosphere functional assay;586
13.3.4.3;Is there a brain neoplasm stem cell?;587
13.3.4.4;Induced pluripotent stem cells, reprogramming and directed differentiation;587
13.3.5;Stem Cells Offer Potential for Repair in the Adult Nervous System;588
13.3.5.1;Stem cells to replace depleted neurochemicals: Parkinson’s disease;588
13.3.5.2;Stem cell treatment to deliver missing enzymes or proteins: leukodystrophies;589
13.3.5.3;Stem cells for cell replacement therapy: myelin;589
13.3.5.4;Stem cells as a source of growth factors and guidance cues;590
13.3.5.5;Stem cells for immunomodulation: multiple sclerosis;591
13.3.5.6;Common challenges 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
13.4.1.1;Myelination occurs during nervous system development and is essential for normal nervous system function;595
13.4.2;Schwann Cell Development;595
13.4.2.1;Schwann cells are the myelinating cells of the peripheral nervous system;595
13.4.2.2;Schwann cell lineage differentiation is regulated by a series of transcription factors;595
13.4.3;Oligodendrocyte Development;595
13.4.3.1;Oligodendrocytes are the myelinating cells of the CNS;595
13.4.3.2;Much early work was possible because of in vitro analysis of the oligodendrocyte cell lineage;595
13.4.3.3;The discovery of several transcription factors that are expressed at early stages of oligodendrocyte specification and…;596
13.4.3.4;A number of transcriptional and epigenetic regulators control oligodendrocyte progenitor cell differentiation into…;597
13.4.4;Regulation of Myelination;599
13.4.4.1;Extensive recent research has focused on identifying the axonal signals that regulate myelination;599
13.4.5;Developmental and Metabolic Aspects of Myelin;600
13.4.5.1;Synthesis of myelin components is very rapid during deposition of myelin;600
13.4.5.2;Sorting and transport of lipids and proteins takes place during myelin assembly;600
13.4.5.3;The composition of myelin changes during development;601
13.4.6;Genetic Disorders of Myelination;601
13.4.6.1;Rodent mutants of myelination have been investigated since the 1950s;601
13.4.7;Myelin Maintenance;602
13.4.7.1;Maintenance of myelin once it is formed is a poorly understood process;602
13.4.7.2;Myelin components exhibit great heterogeneity of metabolic turnover;602
13.4.7.3;There are signal transduction systems in myelin sheaths;602
13.4.7.4;The dynamic nature of myelin sheaths likely contributes to the functional state of axons;603
13.4.7.5;Peripheral neuropathies result from loss of myelin in the peripheral nervous system;603
13.4.7.6;A number of environmental toxins impact myelination during development or myelin maintenance in the adult;603
13.4.7.7;Leukodystrophies define a number of genetic disorders that impact CNS myelination (dysmyelination) or myelin maintenance once…;603
13.4.8;Remyelination;604
13.4.8.1;Peripheral nerve regeneration has been studied extensively;604
13.4.8.2;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
13.5.2.1;Wallerian degeneration is the secondary disruption of the myelin sheath and axon distal to the injury;608
13.5.2.2;The molecular and cellular events during Wallerian degeneration in the PNS transform the damaged nerve into an environment…;608
13.5.2.3;Both Schwann cells and basal lamina are required for axonal regeneration to proceed;609
13.5.2.4;Cell surface adhesion molecules, which promote regeneration, are expressed on plasmalemma of both Schwann cells and regenerating…;610
13.5.2.5;Structural and biochemical changes occur after axotomy;610
13.5.3;Regeneration in the Central Nervous System;610
13.5.3.1;Central nervous system myelin contains molecules that inhibit neurite growth;610
13.5.3.2;Nogo-A is a potent inhibitor of neurite growth and blocks axonal regeneration in the central nervous system;611
13.5.3.3;Nogo gene is a member of the reticulon superfamily;612
13.5.3.4;Nogo-A function-blocking antibodies and peptides lead to axonal growth and functional recovery in vivo;613
13.5.3.5;Lines of knockout mice null for the Nogo genes have been developed;613
13.5.3.6;Additional myelin components have growth-inhibitory activity;613
13.5.3.7;Inhibition of neurite growth is mediated through surface receptors and intracellular signaling molecules;614
13.5.3.8;Neuronal expression of Nogo-A regulates neurite outgrowth;614
13.5.3.9;Axon growth is inhibited by the glial scar;614
13.5.3.10;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
13.5.4.1;Neonatal brain damage results in compensatory plasticity;615
13.5.4.2;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
14.1.1.1;Definition: What is neuroimmunology?;622
14.1.1.2;Scope: Are neuroimmune interactions relevant only in the context of immune-mediated neurodegenerative disorders?;623
14.1.1.3;Relevance: A real-world example;623
14.1.2;Distinguishing Friend from FOE;624
14.1.2.1;Innate versus adaptive immunity: two interacting types of immune recognition;624
14.1.2.1.1;Innate immunity is triggered by evolutionarily conserved alarm signals;624
14.1.2.1.2;Adaptive immunity can recognize evolutionarily novel molecules;624
14.1.2.1.3;Antigen presentation by major histocompatibility-complex–expressing cells is required to activate T-cells;624
14.1.2.1.4;Antigen-activated T-cells regulate the activation of innate immune cells;626
14.1.2.1.5;The activation state of the antigen-presenting cell regulates T cell activation and phenotype;626
14.1.2.2;Choosing between immune tolerance and inflammation;626
14.1.2.2.1;Antigen presentation in the absence of alarm signals promotes tolerance;627
14.1.2.2.2;PAMP and DAMP signals shape APC function and T-cell differentiation;627
14.1.3;The Nervous System Regulates Both Innate and Adaptive Immunity;627
14.1.3.1;Functional consequences of lymphoid tissue innervation;627
14.1.3.2;Neuropeptides are potent modulators of antigen-presenting cell function;628
14.1.4;Immune Privilege Is Not Immune Isolation: The CNS as an Immune-Active Organ;628
14.1.4.1;The BBB and CNS-specific regulation of leukocyte influx and efflux;629
14.1.4.2;Leukocyte migration into the CNS parenchyma is a two-step process;629
14.1.4.3;Microglia, a CNS-specific macrophage and antigen-presenting cell;630
14.1.4.3.1;Distinguishing CNS-resident microglia from CNS-infiltrating macrophages;630
14.1.4.3.2;Microglia are not effective at initiating antigen-driven T-cell functions;631
14.1.4.4;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
14.2.1.1;The role of microglia in neuroinflammation;636
14.2.2;The Highly Regulated Activation of Microglia and Phagocytosis;637
14.2.2.1;Microglial activation;637
14.2.2.2;Microglial phagocytosis;637
14.2.2.3;Receptors in microglia;637
14.2.2.4;Microglia in neurodegenerative diseases;638
14.2.3;Microglial Dysfunction During Aging;638
14.2.4;Protein Aggregation;638
14.2.4.1;The effects of protein aggregation on microglial function;639
14.2.5;Cytokines/Chemokines;639
14.2.5.1;Cytokines are responsible for microglia activation;639
14.2.5.2;Cytokines are produced by activated microglia;639
14.2.5.3;Anti-inflammatory interleukin-10 and TGF-ß1;639
14.2.6;Lipid Mediator Pathways in Neuroinflammation;639
14.2.6.1;Initiation of inflammation: prostaglandin and leukotriene pathways;639
14.2.6.2;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
14.2.8.1;Aß Immunotherapy;641
14.2.8.2;The inflammasome;641
14.2.9;Mitochondria: A Connection Between Inflammation and Neurodegeneration;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
14.3.1.1;Focal cerebral ischemia;647
14.3.1.2;Global cerebral ischemia;648
14.3.2;Injury in the Ischemic Phase;652
14.3.2.1;Excitotoxic glutamate neurotransmitter;652
14.3.2.2;Excitotoxicity;652
14.3.2.3;Ca2+ overloading in the ischemic injury;652
14.3.2.4;NMDA receptors, brain function and cell death;653
14.3.2.5;Downstream cell death signals of NMDA receptors;654
14.3.3;Brain Injury During the Reperfusion Phase: Free Radicals in Ischemia–Reperfusion Injury;654
14.3.3.1;Reactive oxygen species contribute to the injury;654
14.3.3.2;Mitochondria, nitric oxide synthase and polyunsaturated fatty acid metabolism are sources of reactive oxygen species during…;655
14.3.3.3;Polyunsaturated fatty acids generate reactive oxygen species;655
14.3.3.4;Brain antioxidants contribute to the protection of brain from ischemia–reperfusion injury;655
14.3.3.5;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
14.3.4.1;Metalloproteinases during the neurovascular unit disruption;656
14.3.4.2;Significance of aquaporins in brain edema;657
14.3.5;Neuroprotection Signaling and Resolution of Inflammation: Mechanisms;657
14.3.5.1;Inflammatory mediators and anti-inflammatory regulation;657
14.3.5.2;Apoptotic signaling;658
14.3.5.3;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
14.4.1.1;Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli;669
14.4.1.2;Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli;670
14.4.1.3;Phospholipids in synaptic membranes are an important target in seizures, traumatic brain injury, neurodegenerative diseases…;670
14.4.1.4;Some molecular species of phospholipids in excitable membranes are reservoirs of bioactive lipid mediators that act as…;670
14.4.1.5;Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second…;670
14.4.2;Phospholipases A2;672
14.4.2.1;Phospholipases A2 catalyze the cleavage of the fatty acyl chain from the sn-2 carbon of the glycerol backbone of phospholipids;672
14.4.2.2;Cytosolic phospholipases A2 are involved in bioactive lipid formation;672
14.4.2.3;Ischemia and seizures activate phospholipases A2, releasing arachidonic and docosahexaenoic acids;672
14.4.2.4;Secretory phospholipases A2 are of relatively low molecular weight and have a high number of disulfide bridges, making them…;672
14.4.2.5;There are high-affinity receptors that bind secretory phospholipases A2;672
14.4.3;Eicosanoids;673
14.4.3.1;Arachidonic acid is converted to biologically active derivatives by cyclooxygenases and lipoxygenases;673
14.4.3.2;Prostaglandins are very rapidly released from neurons and glial cells;673
14.4.3.3;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
14.4.4.1;Platelet-activating factor is a very potent and short-lived lipid messenger;675
14.4.4.2;Ischemia and seizures increase platelet-activating factor content in the brain;677
14.4.5;Cyclooxygenases;677
14.4.5.1;The cyclooxygenases are heme-containing enzymes that convert arachidonic acid to prostaglandin H2;677
14.4.5.2;Platelet-activating factor is a transcriptional activator of cyclooxygenase-2;677
14.4.5.3;COX-derived AA metabolites play multiple important roles in CNS;677
14.4.5.4;Cyclooxygenase-2 participates in aberrant synaptic plasticity during epileptogenesis;677
14.4.6;Lipoxygenases;678
14.4.6.1;The lipoxygenases are involved in the rate-determining step in the biosynthesis of leukotrienes, lipoxins, resolvins, and protectins;678
14.4.6.2;5-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 5-position to form 5-HpETE;678
14.4.6.3;15-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 15-position to Form 15-HpETE;678
14.4.6.4;LOs and LO-derived products play important roles in a variety of inflammatory disorders;679
14.4.7;Diacylglycerol Kinases;679
14.4.7.1;The slow glutamate responses are mediated through metabotropic receptors coupled to G proteins;679
14.4.8;Lipid Signaling in Neuroinflammation;679
14.4.8.1;A platelet-activating-factor-stimulated signal-transduction pathway is a major component of the kainic-acid-induced…;679
14.4.8.2;In cerebrovascular diseases, the phospholipase-A2-related signaling triggered by ischemia–reperfusion may be part of a delicate…;679
14.4.8.3;Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, are products of membrane lipid breakdown…;679
14.4.8.4;Free fatty acid release during cerebral ischemia is a complex process that includes the activation of signaling cascades;680
14.4.8.5;The rate of free fatty acid production in the mammalian brain correlates with the extent of resistance to ischemia;681
14.4.8.6;Activation of the arachidonic acid cascade during ischemia–reperfusion is a multistage process;681
14.4.8.7;Cyclooxygenase and lipoxygenase products accumulate during reperfusion following cerebral ischemia;681
14.4.8.8;The cerebrovasculature is also an abundant source of eicosanoids;681
14.4.9;Docosahexaenoic Acid;681
14.4.9.1;Brain and retina are the tissues containing the highest contents of docosahexaenoic acid;681
14.4.9.2;Rhodopsin in photoreceptors is immersed in a lipid environment highly enriched in phospholipids containing docosahexaenoic…;681
14.4.10;Lipid Peroxidation and Oxidative Stress;682
14.4.10.1;Docosahexaenoic-acid–containing phospholipids are targets for lipid peroxidation;682
14.4.11;Docosanoids;682
14.4.11.1;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-Acid–Derived Mediator;682
14.4.12.1;Docosanoids, enzyme-derived docosahexaenoic acid metabolites, were identified initially in the retina;682
14.4.12.2;Neuroprotectin D1 is a potent inhibitor of brain ischemia–reperfusion-induced PMN infiltration, as well as of NF-.B and COX-2 expression;682
14.4.13;The Future of Neurolipidomic Signaling;682
14.4.13.1;Knowledge of the significance of lipid signaling in the nervous system is being expanded by advances in experimental approaches;682
14.4.13.2;Understanding of the fundamental workings of the dendrites, which contain complex intracellular membranes rich in polyunsaturated…;683
14.4.13.3;Arachidonic acid is widely implicated in signaling in brain, and research continues toward understanding the release of this fatty…;683
14.4.13.4;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
14.5.1.1;During embryonic and postnatal development, and throughout adult life, many cells in the nervous system die;688
14.5.1.2;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
14.5.2.1;Adaptive apoptosis occurs in the developing and adult nervous system;689
14.5.2.2;Apoptosis occurs in acute neurological insults;690
14.5.2.3;Apoptosis occurs in neurodegenerative disorders;692
14.5.2.4;There are many triggers of apoptosis;693
14.5.2.4.1;Insufficient trophic support;693
14.5.2.4.2;Death receptor activation;693
14.5.2.4.3;DNA damage;693
14.5.2.4.4;Oxidative and metabolic stress;693
14.5.2.5;Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process;694
14.5.2.6;Several different changes in mitochondria occur during apoptosis;695
14.5.2.7;The postmitochondrial events of apoptosis include activation of the caspases;695
14.5.2.8;A widely used criterion for identifying a cell as ‘apoptotic’ is nuclear chromatin condensation and fragmentation;695
14.5.2.9;Cells in the nervous system possess different mechanisms to prevent apoptosis;695
14.5.2.9.1;Neurotrophic factors, cytokines and cell adhesion molecules;695
14.5.2.9.2;Antiapoptotic proteins;696
14.5.2.9.3;Hormesis-based mechanisms;696
14.5.2.9.4;Antioxidants and calcium-stabilizing proteins;696
14.5.2.10;The morphological and biochemical characteristics of apoptosis are not always manifest in cells undergoing programmed cell ...;697
14.5.2.11;Apoptotic cascades can be triggered, and pre- and postmitochondrial events can occur, without the cell dying;697
14.5.3;Necrosis;697
14.5.3.1;Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates;697
14.5.3.2;There are few cell death triggers that are only capable of inducing either apoptosis or necrosis;697
14.5.3.2.1;Trauma;697
14.5.3.2.2;Energy failure/ischemia;697
14.5.3.2.3;Excitotoxicity;698
14.5.4; TARGETING Apoptosis and Necrosis in Neurological DISORDERS;698
14.5.5;References;700
15;VI. INHERITED AND NEURODEGENERATIVE DISEASES;702
15.1;38. Peripheral Neuropathy: Neurochemical and Molecular Mechanisms;704
15.1.1;Introduction;704
15.1.2;Peripheral Nerve Organization;705
15.1.2.1;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
15.1.3.1;The inherited neuropathies are commonly referred to as Charcot-Marie-Tooth disorders (CMT) or hereditary motor and sensory…;705
15.1.4;Diabetic Neuropathy;709
15.1.4.1;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
15.1.5.1;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
15.1.6.1;Infections can damage nerves directly, via exotoxins, or by immune mechanisms;712
15.1.6.2;Peripheral nerve damage is a recognized complication of toxins (e.g., alchohol, heavy metals, hexacarbons, organophosphates…;712
15.1.6.3;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
15.2.1.1;Myelin deficiency can result from failure of synthesis during development or from myelin breakdown after its formation;717
15.2.1.2;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
15.2.2.1;Nervous system damage in acquired demyelinating diseases is selectively against myelin or myelin-forming cells, but axons…;717
15.2.2.2;Multiple sclerosis (MS) is the most common demyelinating disease of the CNS in humans;717
15.2.2.2.1;Diagnosis;717
15.2.2.2.2;Pathology;718
15.2.2.2.3;Gray matter lesions;718
15.2.2.2.4;Axonal and neuronal pathology;719
15.2.2.2.5;Biochemistry;719
15.2.2.2.6;Therapy;720
15.2.2.2.7;Etiology;720
15.2.2.2.8;Epidemiology and natural history of MS;720
15.2.2.2.9;Environmental factors;720
15.2.2.2.10;Genetics;721
15.2.2.2.11;Immunology;721
15.2.2.2.12;Perspectives for future research;721
15.2.2.3;Animal models are required to understand the pathogenesis of MS and test the efficacy of possible therapeutic interventions;721
15.2.2.3.1;Viral models;721
15.2.2.3.2;Experimental allergic encephalomyelitis;722
15.2.2.3.3;Toxins;722
15.2.2.4;Other acquired disorders affecting CNS myelin have an immune-mediated or infectious pathogenesis;722
15.2.2.4.1;Acute disseminated encephalomyelitis;722
15.2.2.4.2;Progressive multifocal leukoencephalopathy;722
15.2.2.5;Some human peripheral neuropathies involving demyelination are immune mediated;722
15.2.2.5.1;Paraproteinemic polyneuropathy;723
15.2.2.5.2;Guillain–Barré syndrome;723
15.2.2.5.3;Chronic inflammatory demyelinating polyneuropathy;724
15.2.3;Genetically Determined Disorders of Myelin;724
15.2.3.1;The human leukodystrophies are inherited disorders of CNS white matter;724
15.2.3.1.1;Lysosomal storage diseases;724
15.2.3.1.2;Other leukodystrophies;726
15.2.3.2;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
15.2.4.1;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
15.2.5.1;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
15.2.6.1;The capacity for remyelination depends upon the presence of receptive axons and sufficient myelin-forming cells;727
15.2.6.2;Spontaneous remyelination of lesions of MS is well documented, but remyelination is usually incomplete;728
15.2.6.3;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
15.3.2.1;Disrupting the delicate balance of inhibitory and excitatory synaptic transmission can trigger the disordered, synchronous…;731
15.3.2.2;Cellular mechanisms underlying hyperexcitability have been analyzed by electrophysiological studies of hippocampal slices…;733
15.3.2.3;Normally the dentate granule cells of hippocampus limit excessive activation of their targets, the CA3 pyramidal cells;733
15.3.2.4;Analyses of afferents of dentate granule cells from epileptic animals reveal abnormal inhibitory and excitatory synaptic input;734
15.3.2.5;Axonal and dendritic sprouting lead to abnormal recurrent excitatory synaptic circuits among the dentate granule cells in epileptic brain;734
15.3.2.6;Epileptogenesis is the process by which a normal brain becomes epileptic;734
15.3.2.7;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
15.3.3.1;Many antiseizure drugs act on voltage-gated sodium channels to limit high-frequency, but not low-frequency, firing of neurons;736
15.3.3.2;Other antiseizure drugs enhance GABA-mediated synaptic inhibition;736
15.3.3.3;Other antiseizure drugs regulate a subset of voltage-gated calcium currents;737
15.3.4;Genetics of Epilepsy;738
15.3.4.1;Many forms of epilepsy have genetic determinants;738
15.3.4.2;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;Alzheimer’s Disease;746
15.4.2.1;Early onset familial AD;746
15.4.2.2;Apolipoprotein E in late-onset AD;746
15.4.2.3;Genome-wide screening in late-onset AD;747
15.4.3;Parkinson’s Disease;748
15.4.3.1;Autosomal-dominant forms of PD;748
15.4.3.2;Autosomal-recessive forms of PD;748
15.4.3.3;Candidate-gene studies and genome-wide screening in PD;749
15.4.4;Dementia with Lewy Bodies;750
15.4.4.1;The genetics of DLB shows similarities with both PD and AD;750
15.4.5;Frontotemporal Dementia;751
15.4.5.1;Genetic determinants of tau-positive FTLD;751
15.4.5.2;Genetic determinants of tau-negative FTLD;751
15.4.6;Amyotrophic Lateral Sclerosis;752
15.4.6.1;Familial ALS;752
15.4.7;Neurodegenerative Triplet Repeat Disorders;754
15.4.7.1;Huntington’s disease (HD);754
15.4.8;Creutzfeld-JaKob Disease and other Prion Diseases;755
15.4.8.1;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
15.5.1.1;An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid;763
15.5.1.2;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
15.5.1.3;Untreated aminoacidurias can cause brain damage in many ways, often through impairing brain energy metabolism;763
15.5.1.4;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
15.5.1.5;Treatment of aminoacidurias with a low-protein diet may influence brain chemistry;767
15.5.1.6;Imbalances of brain amino acids may hinder the synthesis of brain lipids, leading to a diminution in the rate of myelin formation;767
15.5.1.7;In many aminoacidurias, there may occur deficits in neurotransmitters and receptors, particularly the N-methyl-d-aspartate receptor;767
15.5.1.8;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
15.5.2.1;Maple syrup urine disease involves a congenital failure to oxidize the three branched-chain amino acids;767
15.5.2.2;Effective treatment of maple syrup urine disease involves the restriction of dietary branched-chain amino acids;768
15.5.3;Disorders of Phenylalanine Metabolism: Phenylketonuria;768
15.5.3.1;Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase;768
15.5.3.2;The outlook for patients who are treated at an early age is favorable;769
15.5.3.3;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
15.5.4.1;Nonketotic hyperglycinemia results from the congenital absence of the glycine cleavage system, which mediates the interconversion of glycine and serine;769
15.5.4.2;Nonketotic hyperglycinemia causes a severe seizure disorder and profound brain damage;769
15.5.4.3;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
15.5.5.1;The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids;770
15.5.5.2;Homocystinuria is the result of the congenital absence of cystathionine synthase, a key enzyme of the transsulfuration pathway;772
15.5.5.3;Homocystinuria can be treated in some cases by the administration of pyridoxine (Vitamin B6), which is a cofactor for the cystathionine synthase reaction;772
15.5.5.4;Patients with homocystinuria are at risk for cerebrovascular and cardiovascular disease and thromboses;772
15.5.5.5;Prognosis is more favorable in the pyridoxine-responsive patients;772
15.5.5.6;Homocystinuria can occur when homocysteine is not remethylated back to form methionine;773
15.5.5.7;One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine;773
15.5.5.8;Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria;773
15.5.5.9;Cobalamin-c disease: remethylation of homocysteine to methionine also requires an ‘activated’ form of vitamin B12;773
15.5.5.10;Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration;774
15.5.6;The Urea Cycle Defects;774
15.5.6.1;The urea cycle is essential for the detoxification of ammonia;774
15.5.6.2;Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant;775
15.5.6.2.1;Carbamyl phosphate synthetase deficiency;775
15.5.6.2.2;N-Acetylglutamate synthetase deficiency;775
15.5.6.2.3;Ornithine transcarbamylase deficiency;775
15.5.6.2.4;Citrullinemia;775
15.5.6.2.5;Argininosuccinic aciduria;776
15.5.6.2.6;Arginase deficiency;776
15.5.6.3;Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle;776
15.5.6.3.1;Hyperornithinemia, hyperammonemia, homocitrullinuria;776
15.5.6.3.2;Lysinuric protein intolerance;776
15.5.6.4;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
15.5.7.1;The tripeptide glutathione is the major intracellular antioxidant;777
15.5.7.1.1;5-Oxoprolinuria: glutathione synthetase deficiency;777
15.5.7.1.2;.-Glutamylcysteine synthetase deficiency;777
15.5.7.1.3;.-Glutamyltranspeptidase deficiency;777
15.5.7.1.4;5-Oxoprolinase deficiency;777
15.5.8;Disorders of g-Aminobutyric Acid Metabolism;777
15.5.8.1;Congenital defects in the metabolism of .-aminobutyric acid have been described;777
15.5.8.1.1;Pyridoxine dependency;778
15.5.8.1.2;.-Aminobutyric acid transaminase deficiency;778
15.5.8.1.3;Succinic semialdehyde dehydrogenase deficiency;778
15.5.9;Disorders of N-Acetyl Aspartate Metabolism;778
15.5.9.1;Canavan’s 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 Lysosomes, Peroxisomes, Carbohydrates, Fatty Acids and Mitochondria;780
15.6.1;Lysosomal Storage Diseases;780
15.6.1.1;The cell contains specialized organelles for the recycling of waste material: the lysosomes;780
15.6.1.2;Deficiency of a lysosomal enzyme causes the blockage of the corresponding metabolic pathway, leading to the accumulation of its undigested substrate;781
15.6.1.3;For most lysosomal storage diseases, definitive cures are not available;782
15.6.1.4;Lysosomal storage disorders are pleiotropic, depending on the mutation, the enzyme affected and the sites of accumulated products;782
15.6.1.4.1;Farber disease;782
15.6.1.4.2;Gaucher disease;782
15.6.1.4.3;Krabbe disease (globoid cell leukodystrophy);783
15.6.1.4.4;Metachromatic leukodystrophy (MLD);783
15.6.1.4.5;Fabry disease;784
15.6.1.4.6;GM2 gangliosidoses (Tay–Sachs disease; Sandhoff disease and GM2 activator deficiency);784
15.6.1.4.7;Niemann–Pick disease, types A and B;785
15.6.1.4.8;Niemann–Pick disease type C (NPC);785
15.6.1.4.9;The mucopolysaccharidoses (MPS);785
15.6.1.4.10;Neuronal ceroid lipofuscinoses (NCLs);785
15.6.2;Peroxisomal Diseases;785
15.6.2.1;Peroxisomes are specialized organelles for metabolism of oxygen peroxide and of various lipids;785
15.6.2.2;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
15.6.3.1;Human diseases involving peroxisomal dysfunction were originally described as syndromes;786
15.6.3.1.1;Defects of peroxisomal biogenesis;786
15.6.3.1.2;Defects of single peroxisomal enzymes;786
15.6.4;Therapy of Peroxisomal Diseases;787
15.6.5;Diseases of Carbohydrate and Fatty Acid Metabolism;787
15.6.5.1;Diseases of carbohydrate and fatty acid metabolism in muscle;788
15.6.5.1.1;One class of glycogen or lipid metabolic disorders in muscle is manifest as acute, recurrent, reversible dysfunction;788
15.6.5.1.2;Phosphorylase deficiency (McArdle disease, glycogenosis type V) exemplifies the glycogenoses causing recurrent muscle “energy crises,” with cramps, myalgia…;788
15.6.5.1.3;Genetic defects of phosphorylase b kinase (PHK);788
15.6.5.1.4;Other glycolytic defects involving PFK, PGK, PGAM, and LDH have clinical and pathological features similar to McArdle disease;789
15.6.5.1.5;CPT II deficiency has clinical features similar to McArdle disease;791
15.6.5.1.6;Other beta-oxidation defects have clinical features similar to McArdle disease;791
15.6.5.1.7;A second class of disorders of glucose and fatty acid metabolism causes progressive weakness;791
15.6.5.1.8;Acid maltase deficiency (AMD) (glycogenosis type II);791
15.6.5.1.9;Debrancher enzyme deficiency (glycogenosis type III, Cori’s disease, Forbe disease);792
15.6.5.1.10;Branching enzyme deficiency (glycogenosis type IV; Andersen’s disease);792
15.6.5.1.11;Carnitine deficiency;792
15.6.5.1.12;Defects in adipose triglyceride lipase (ATGL);793
15.6.5.2;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
15.6.5.3;Diseases of carbohydrate and fatty acid metabolism in brain;795
15.6.5.3.1;Defective transport of glucose across the blood–brain barrier is caused by deficiency in the glucose transporter protein;795
15.6.5.3.2;One class of carbohydrate and fatty acid metabolism disorders is caused by defects in enzymes that function in the brain;795
15.6.5.3.3;Debrancher enzyme deficiency;795
15.6.5.3.4;Branching enzyme deficiency;795
15.6.5.3.5;Phosphoglycerate kinase deficiency;796
15.6.5.3.6;Lafora disease;796
15.6.5.3.7;Another class of carbohydrate and fatty acid metabolism disorders is caused by systemic metabolic defects that affect the brain. Glucose-6-phosphatase deficiency (glycogenosis type I, Von Gierke disease);796
15.6.5.3.8;Fructose-1,6-bisphosphatase deficiency;796
15.6.5.3.9;Phosphoenolpyruvate carboxykinase (PEPCK) deficiency;796
15.6.5.3.10;Pyruvate carboxylase deficiency;796
15.6.5.3.11;Biotin-dependent syndromes;797
15.6.5.3.12;Glycogen synthetase deficiency;797
15.6.5.3.13;Fatty acid oxidation defects;797
15.6.6;Diseases of Mitochondrial Metabolism;797
15.6.6.1;Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system;797
15.6.6.2;Mitochondrial DNA is inherited maternally;798
15.6.6.3;The genetic classification of mitochondrial diseases divides them into three groups;799
15.6.6.3.1;Defects of nuclear DNA;799
15.6.6.4;Defects of communication between nDNA and mtDNA can also cause mitochondrial diseases;800
15.6.6.4.1;Defects in genes controlling mtDNA translation;800
15.6.6.5;The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism;800
15.6.6.5.1;Defects of mitochondrial transport;800
15.6.6.5.2;Defects of substrate utilization;800
15.6.6.5.3;Defects of the Krebs cycle;801
15.6.6.5.4;Defects of oxidation—phosphorylation Coupling;801
15.6.6.5.5;Abnormalities of the respiratory chain;801
15.6.6.5.6;Abnormalities of the respiratory chain: defects of complex I;801
15.6.6.5.7;Abnormalities of the respiratory chain: defects of complex II;802
15.6.6.5.8;Abnormalities of the respiratory chain: coenzyme Q10 (CoQ10) deficiency;802
15.6.6.5.9;Abnormalities of the respiratory chain: defects of complex III;802
15.6.6.5.10;Abnormalities of the respiratory chain: defects of complex IV;802
15.6.6.5.11;Abnormalities of the respiratory chain: defects of complex V;803
15.6.7;Acknowledgments and Dedication;804
15.6.8;References;804
15.7;44. Disorders of Muscle Excitability;808
15.7.1;Organization of the Neuromuscular Junction;808
15.7.1.1;Nerve and muscle communicate through neuromuscular junctions;808
15.7.1.2;Acetylcholine acts as a chemical relay between the electrical potentials of nerve and muscle;810
15.7.1.3;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
15.7.2.1;The excitable apparatus of muscle is composed of membranous compartments;811
15.7.2.2;Myofibrils are designed and positioned to produce movement and force;811
15.7.2.3;Calcium couples muscle membrane excitation to filament contraction;812
15.7.3;Genetic Disorders of the Neuromuscular Junction;814
15.7.3.1;Congenital myasthenic syndromes impair the operation of the acetylcholine receptor;814
15.7.3.1.1;ChAT Deficiency;814
15.7.3.1.2;AChR Deficiency;814
15.7.3.1.3;Rapsyn deficiency;815
15.7.3.1.4;Slow channel syndrome;815
15.7.3.1.5;Fast channel syndrome;815
15.7.3.1.6;Acetylcholinesterase deficiency;815
15.7.4;Hereditary Diseases of Muscle Membranes;815
15.7.4.1;Mutations of the sodium channel cause hyperkalemic periodic paralysis and paramyotonia congenital;815
15.7.4.2;Hypokalemic periodic paralysis is due to calcium channel mutations;816
15.7.4.3;Abnormal potassium channels in Andersen syndrome cause more than periodic paralysis;816
15.7.4.4;Ribonuclear inclusions are responsible for the multiple manifestations of myotonic dystrophy;816
15.7.4.5;Congenital myotonia is caused by mutant Cl- channels;817
15.7.4.6;Malignant hyperthermia caused by mutant ryanodine receptor calcium release channels;817
15.7.4.7;Calcium channel mutations may also cause malignant hyperthermia;818
15.7.4.8;Brody disease is an unusual disorder of the sarcoplasmic reticulum calcium ATPase;818
15.7.5;Immune Diseases of Muscle Excitability;818
15.7.5.1;Myasthenia gravis is caused by antibodies that promote premature AChR degradation;818
15.7.5.2;Antibodies against MuSK mimic myasthenia gravis;818
15.7.5.3;Antibodies cause calcium channel dysfunction in Lambert-Eaton syndrome;819
15.7.5.4;Potassium channel antibodies in Isaac syndrome cause neuromyotonia;819
15.7.6;Toxins and Metabolites that Alter Muscular Excitation;820
15.7.6.1;Bacterial botulinum toxin blocks presynaptic ACh release;820
15.7.6.2;Snake, scorpion, spider, fish and snail peptide venoms act on multiple molecular targets at the neuromuscular junction;821
15.7.6.3;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
15.8.1.1;The disease is characterized clinically by weakness, muscle atrophy and spasticity affecting both upper and lower motor neurons;827
15.8.1.2;Although most cases ALS are sporadic, mutations in several genes may cause familial ALS;828
15.8.1.2.1;ALS1 is caused by mutant SOD1;828
15.8.1.2.2;ALS2 is linked to mutant Alsin;828
15.8.1.2.3;ALS4 is linked to mutations in a helicase gene;828
15.8.1.2.4;Angiogenic factors may be linked to ALS;828
15.8.1.2.5;Mutant dynactin p150Glued causes fALS;829
15.8.1.2.6;VAPB associated with ALS is a ligand for eph receptors;829
15.8.1.2.7;ALS is linked to two genes involved in RNA metabolism: TDP-43 and FUS;829
15.8.1.2.8;Mutations in OPTN were identified in several japanese patients with ALS;830
15.8.1.2.9;Identification of valosin-containing protein (VCP) is linked to fALS by exome sequencing;831
15.8.2;Models of Motor Neuron Disease Induced by Experimental Nerve Injury Have been Instructive;831
15.8.2.1;Interrupting the communication between the motor neuron cell body and axon by transection, crush or avulsion induces motor neuron injury;831
15.8.2.2;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
15.8.3.1;Hereditary canine spinal muscular atrophy (HCSMA) is a naturally occurring mutation that produces motor neuron disease;831
15.8.3.2;Some transgenic mice expressing wild-type or mutant NF genes develop motor neuron disease and neurofibrillary pathology;832
15.8.3.3;fALS-linked mutant SOD1 mice reproduce many of the clinical and pathological features of ALS;832
15.8.3.4;Lines of mice harboring other mutant genes may also develop an ALS-like phenotype;832
15.8.3.4.1;Mutant dynactin p150glued transgenic mice have MND-like pathology;833
15.8.3.4.2;Mutant tubulin-specific chaperone E transgenic mice exhibit progressive motor neuropathy;833
15.8.3.4.3;To test the role of NF in mutant SOD1 mice, the latter animals were crossbred to several lines of mice that have altered distributions of NF;833
15.8.3.4.4;Vascular endothelial growth factor (VEGF) influences the growth and permeability of blood vessels;833
15.8.3.5;The molecular mechanisms whereby mutant SOD1 causes selective motor neuron death have yet to be defined;833
15.8.3.5.1;Is the toxicity of mutated SOD1 cell-autonomous?;833
15.8.3.5.2;Expression of GLT1 is implicated as a possible cofactor;833
15.8.3.5.3;Mutation-induced conformational effects and copper oxidative toxicity have been implicated;834
15.8.3.5.4;Accumulating evidence supports the view that fALS-associated mutants facilitate misfolding of wild-type SOD1;834
15.8.3.6;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 Alzheimer’s Disease;840
15.9.1;Alzheimer’s Disease is the Most Prevalent Neurodegenerative Disease of the Elderly;840
15.9.1.1;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
15.9.1.2;Advances in laboratory measurements and imaging are of value in establishing the diagnosis of AD;841
15.9.1.3;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
15.9.1.3.1;APP Mutations are Linked to fAD;842
15.9.1.3.2;Mutations in PS1 and PS2 are Linked to fAD;842
15.9.1.4;Multiple neurotransmitter circuits and brain networks are damaged in AD;842
15.9.1.5;Neuritic plaques, one of the pathological hallmarks of AD, are composed of swollen neurites, extracellular deposits of Aß 40-42 peptides derived from…;843
15.9.1.6;Neurofibrillary tangles (NFT), another characteristic feature of AD, are composed of intracellular bundles of paired helical filaments (PHF), which represent…;843
15.9.1.7;Aspartyl proteases carry out the ß- and g-secretase cleavages of APP to generate Aß peptides;844
15.9.1.8;Transgenic strategies have been used to create models of Aß amyloidosis and tauopathies;845
15.9.1.9;Gene targeting approaches have identified and validated targets for therapy;846
15.9.1.10;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
15.10.2.1;The human synuclein family consists of three members;855
15.10.2.2;Synucleins are lipid-binding proteins;855
15.10.3;Parkinson’s Disease and Other Lewy Body Diseases;856
15.10.3.1;SNCA mutations cause familial Parkinson’s disease;856
15.10.3.2;Lewy body filaments are made of a-synuclein;856
15.10.3.3;The development of a-synuclein pathology is not random;857
15.10.3.4;Other genes are implicated in Parkinson’s 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
15.10.6.1;Rodents and primates;858
15.10.6.2;Flies, worms and yeasts;859
15.10.7;Synucleinopathies—Outlook;859
15.10.8;Microtubule-Associated Protein Tau;859
15.10.8.1;Six tau isoforms are expressed in adult human brain;859
15.10.8.2;Tau is a phosphoprotein;860
15.10.9;Tau and Alzheimer’s Disease;860
15.10.9.1;The paired helical filament is made of tau protein;860
15.10.9.2;Filamentous tau is hyperphosphorylated;860
15.10.9.3;The development of tau pathology is not random;861
15.10.10;Other Tauopathies;861
15.10.10.1;Other taupathies include progressive supranuclear palsy, corticobasal degeneration and Pick’s disease;861
15.10.11;MAPT Mutations Causing Tauopathy;861
15.10.11.1;FTD is characterized by atrophy of the frontal and temporal lobes of the cerebral cortex, with additional subcortical changes;861
15.10.11.2;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
15.10.14.1;Rodents and fish;863
15.10.14.2;Flies, worms and yeasts;865
15.10.15;Tauopathies—Outlook;866
15.10.16;References;866
15.11;48. Cellular and Molecular Basis of Neurodegeneration in the CAG–Polyglutamine Repeat Diseases;869
15.11.1;Introduction to the CAG–Polyglutamine Repeat Diseases;869
15.11.1.1;CAG repeat expansions are responsible for nine inherited neurodegenerative disorders;869
15.11.1.2;Normal functions of polyglutamine disease proteins;870
15.11.2;Expanded Polyglutamine Tracts Promote Protein Misfolding to Drive Neurotoxicity;870
15.11.2.1;Disease-length polyglutamine tracts adopt a novel, toxic conformation;870
15.11.2.2;Polyglutamine disease proteins form aggregates visible at the light microscope level;870
15.11.2.3;Polyglutamine disease proteins exist as misfolded monomers, oligomers and protofibrils;871
15.11.2.4;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
15.11.3.1;Are polyglutamine tracts substrates for the ubiquitin-proteasome system and autophagy pathways?;871
15.11.3.2;Autophagy pathway involvement in polyglutamine neurodegeneration;872
15.11.3.3;Evidence for autophagy dysfunction in the polyglutamine repeat diseases;874
15.11.4;The Importance of Normal Function in the Polyglutamine Repeat Diseases;874
15.11.4.1;Interference with ataxin-7’s function as a transcription regulatory protein in SCA7;874
15.11.4.2;Ataxin-1 protein complex associations account for SCA1 disease pathogenesis;874
15.11.4.3;Post-translational modifications as determinants of disease;874
15.11.4.4;Phosphorylation;874
15.11.4.5;Acetylation;875
15.11.4.6;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
15.11.6.1;RNA interference knock-down and antisense oligonucleotide knock-down: two approaches;875
15.11.6.2;Indiscriminate gene silencing;876
15.11.6.3;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
15.12.1.1;The basal ganglia are components of larger circuits;881
15.12.1.2;Involvement of the basal ganglia in movement control;882
15.12.1.3;Multiple neurotransmitter systems are found in the basal ganglia;882
15.12.1.3.1;GABA;882
15.12.1.3.2;Glutamate;883
15.12.1.3.3;Acetylcholine;883
15.12.1.3.4;Dopamine;884
15.12.1.3.5;Dopamine–acetylcholine balance;885
15.12.1.4;Adenosine, cannabinoid and neuropeptides function in the basal ganglia;885
15.12.2;Disorders that Involve Basal Ganglia Dysfunction;886
15.12.2.1;Parkinson’s disease is a hypokinetic movement disorder;886
15.12.2.1.1;Pathology;886
15.12.2.1.2;Etiology;886
15.12.2.1.3;Animal models;887
15.12.2.1.4;Pathophysiology;887
15.12.2.1.5;Symptomatic drug treatment of PD;888
15.12.2.1.6;Surgical therapy;889
15.12.2.1.7;Neuroprotective treatment of PD;889
15.12.2.2;Huntington’s disease is a hyperkinetic movement disorder;890
15.12.2.2.1;Genetic and molecular aspects;890
15.12.2.2.2;Animal models;890
15.12.2.2.3;Treatment;890
15.12.2.3;Dystonia is a disorder with involuntary movements;891
15.12.2.3.1;Etiology and classification;891
15.12.2.3.2;Pathophysiology;892
15.12.2.3.3;Treatment;892
15.12.2.4;Neuropsychiatric disorders;892
15.12.2.5;Drugs affecting the basal ganglia;893
15.12.2.5.1;Dopamine depleting agents;893
15.12.2.5.2;Dopamine receptor blocking agents;893
15.12.2.5.3;Tardive syndromes;893
15.12.3;Conclusion;893
15.12.4;References;895
15.13;50. Molecular Basis of Prion Diseases;897
15.13.1;Introduction;898
15.13.2;Prion Diseases are Biologically Unique;898
15.13.2.1;Discovery of the prion protein;898
15.13.2.2;Prion protein is encoded by the host;898
15.13.2.3;Aberrant metabolism of the prion protein is the central feature of prion disease;898
15.13.3;Animal Prion Diseases;898
15.13.3.1;Scrapie and BSE;898
15.13.3.2;Other animal prion diseases;899
15.13.4;Human Prion Diseases;899
15.13.4.1;Human prion disease most commonly presents itself sporadically;899
15.13.4.2;Pathogenic mutations in the prion protein gene cause inherited prion disease;899
15.13.4.3;Acquired human prion diseases include kuru and variant CJD;900
15.13.4.4;Prion protein polymorphism contributes genetic susceptibility to prion disease;900
15.13.4.5;Human prion diseases are clinically heterogeneous;900
15.13.5;Prion Disease Pathology and Pathogenesis;901
15.13.5.1;Peripheral pathogenesis involves the lymphoreticular system;901
15.13.5.2;Prion disease produces characteristic pathology in the central nervous system;901
15.13.6;The Protein-Only Hypothesis of Prion Propagation;902
15.13.6.1;Prion propagation involves conversion of PrPC to PrPSc;902
15.13.7;Characterization of PrPC;902
15.13.7.1;PrPC has a predominantly alpha-helical conformation;902
15.13.7.2;Reverse genetics approaches to studying PrPC;903
15.13.7.3;The function of PrPC remains unknown;903
15.13.7.4;PrP knockout mice have subtle abnormalities;903
15.13.8;Characterization of PrPSc;904
15.13.8.1;PrPSc has a predominantly beta-sheet conformation;904
15.13.8.2;Prion structure remains unknown;904
15.13.8.3;In vitro generation of alternative PrP conformations and prion infectivity;905
15.13.9;The Molecular Basis of Prion Strain Diversity;905
15.13.9.1;Prion strain diversity appears to be encoded by PrP itself;905
15.13.9.2;Distinct PrPSc types are seen in human prion disease;905
15.13.9.3;Difficulties in defining human prion strains;906
15.13.10;Prion Transmission Barriers;907
15.13.10.1;Prion transmission between species is limited by a barrier;907
15.13.10.2;Both PrP sequence and prion strain type influence prion transmission barriers;907
15.13.10.3;A conformational selection model of prion transmission barriers;907
15.13.10.4;Subclinical forms of prion disease pose a risk to public health;907
15.13.10.5;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
16.1.1.1;The visual system is composed of unique structures optimized for collection, detection and processing of visual information;914
16.1.1.2;The retina is composed of highly organized neuronal sublayers;915
16.1.1.3;The ganglion cell axons of the optic nerve carry visual signals from the retina to the brain;915
16.1.1.4;The eye develops as an outcropping of the developing brain;916
16.1.2;Photoreceptors and Phototransduction;917
16.1.2.1;Photoreceptors are polarized cells, with specialized primary cilia, outer segments, devoted to phototransduction;917
16.1.2.2;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
16.1.2.3;Recovery of the dark current after light stimulation is a multistep process mediated by Ca2+ and proteins exerting negative regulation;919
16.1.2.4;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
16.1.3.1;Secondary neurons respond to changes in glutamate release by rods and cones;922
16.1.3.2;ON and OFF bipolar cells use different types of receptors and response mechanisms;922
16.1.3.3;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
16.1.4.1;Rhodopsin regeneration requires a complex series of enzyme-catalyzed reactions in photoreceptors and RPE;923
16.1.4.2;Cones use a visual cycle distinct from that of rods to regenerate pigments;924
16.1.4.3;Retinal pigemented epithelial (RPE) cells promote disk membrane turnover by phagocytosis;924
16.1.5;Retinal Neurodegeneration;924
16.1.5.1;Defects in genes essential for functions of photoreceptors cause retinal degeneration;924
16.1.5.2;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
16.2.1.1;The mammalian olfactory system possesses enormous discriminatory power;929
16.2.1.2;The initial events in olfaction occur in a specialized olfactory neuroepithelium;930
16.2.1.3;The identification and cloning of genes encoding odorant receptors helped to reveal organizational principles of odor coding;930
16.2.1.4;Odor discrimination involves a very large number of different odorant receptors, each responsive to a small set of odorants;931
16.2.1.5;The information generated by hundreds of different receptor types must be organized to achieve a high level of olfactory discrimination;931
16.2.1.5.1;Zonal Expression of Olfactory Receptors;932
16.2.1.5.2;Convergence of Sensory Neurons Onto a few Glomeruli in the Olfactory Bulb;932
16.2.1.6;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
16.2.1.7;Odorant recognition initiates a second-messenger cascade leading to the depolarization of the neuron and the generation of action potentials;932
16.2.1.8;Negative feedback processes mediate adaptation of the olfactory transduction apparatus to prolonged or repetitive stimulation;933
16.2.1.9;Subpopulations of OSNs use alternative olfactory transduction mechanisms;934
16.2.1.10;The vomeronasal organ is an accessory chemosensing system that plays a major role in the detection of semiochemicals;935
16.2.1.11;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
16.2.2.1;Multiple senses, including taste, contribute to our total perception of food;936
16.2.2.2;Taste receptor cells are organized into taste buds;937
16.2.2.3;Sensory afferents within three cranial nerves innervate the taste buds;937
16.2.2.4;Sweet, bitter and umami taste involve G protein-coupled receptors;937
16.2.2.4.1;Type 1 Taste Receptors (T1Rs) Recognize Sweet and Umami Stimuli;937
16.2.2.4.2;Type 2 Taste Receptors (T2Rs) Mediate Responses to Bitter-Tasting Stimuli;938
16.2.2.4.3;T1Rs and T2Rs also Have Important Functions Outside the Gustatory System;938
16.2.2.5;Sweet, bitter and umami tasting stimuli are transduced by a G-protein–coupled signaling cascade;938
16.2.2.6;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
16.3.1.1;Mechanotransduction is of great utility for all organisms;941
16.3.1.2;Models for mechanotransduction allow comparison of mechanoreceptors from many organisms and cell types;941
16.3.2;Non-Vertebrate Model Systems;942
16.3.2.1;Worm mechanoreceptors use a transduction cascade that depends on epithelial sodium channels (ENaC);943
16.3.2.2;Fly mechanoreceptors use molecules similar to those of hair cells;943
16.3.3;Hair Cells;943
16.3.3.1;Hair cells are the sensory cells of the auditory and vestibular systems;943
16.3.3.2;Hair cells are exposed to unusual extracellular fluids and potentials;944
16.3.3.3;Mechanical transduction depends on activation of ion channels linked to extracellular and intracellular structures;945
16.3.3.4;Some of the molecules responsible for transduction have been identified;946
16.3.3.5;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
16.3.5.1;Vestibular organs detect head rotation and linear acceleration;948
16.3.5.2;Hair bundles display varying morphology and physiology;948
16.3.6;Hearing: Cochlea;948
16.3.6.1;The cochlea detects sound and is tonotopically organized;948
16.3.6.2;High-frequency sound detection requires specialized structures and molecules;950
16.3.6.3;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
16.4.2.1;Primary sensory neurons are located in the dorsal root ganglions (DRG) of spinal nerves and the semilunar ganglions of the trigeminal nerves;954
16.4.2.2;Receptor profiles define the response modalities of nociceptors;954
16.4.2.3;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
16.4.3.1;Nociceptive information enters the dorsal horn of the spinal cord;955
16.4.3.2;Signals are modulated by spinal interneurons;955
16.4.4;Brainstem, Thalamus and Cortex;956
16.4.4.1;Nuclei in the brainstem and thalamus, and distinct cortical areas are the major projection targets for nociceptive information;956
16.4.4.2;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
16.4.7.1;Tissue injury produces an “inflammatory soup” of signaling molecules;959
16.4.7.2;Molecular mechanisms involved in peripheral sensitization;959
16.4.7.3;Central sensitization;959
16.4.7.4;Prolonged homosynaptic facilitation;960
16.4.8;Neuropathic Pain;961
16.4.8.1;Paradoxically, nervous system injury may produce not only sensory loss but also chronic pain;961
16.4.8.2;Spontaneous discharges and enhanced excitability of sensory neurons;961
16.4.8.3;Allodynia signals a crossover of sensory modalities;961
16.4.8.4;Central sensitization and descending facilitation;962
16.4.8.5;Disinhibition;962
16.4.8.6;Immune response to nerve injury;963
16.4.9;Genetic Factors;964
16.4.9.1;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
17.1.2.1;The hypothalamic releasing factors regulate release of the anterior pituitary trophic hormones;971
17.1.2.2;Secretion of pituitary hormones is responsive to behavior and effects of experience;971
17.1.2.3;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
17.1.3.1;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
17.1.4.1;Steroid hormones are divided into six classes, based on physiological effects: estrogens, androgens, progestins, glucocorticoids, mineralocorticoids and vitamin D;974
17.1.4.2;Some steroid hormones are converted in the brain to more active products that interact with receptors;974
17.1.4.2.1;The Aromatization of Testosterone;975
17.1.4.2.2;Vitamin D;976
17.1.4.3;Genomic receptors for steroid hormones have been clearly identified in the nervous system;976
17.1.5;Intracellular Steroid Receptors: Properties and Topography;978
17.1.5.1;Steroid hormone receptors are phosphoproteins that have a DNA-binding domain and a steroid-binding domain;978
17.1.5.1.1;Estradiol;978
17.1.5.1.2;Progesterone;978
17.1.5.1.3;Androgen;979
17.1.5.1.4;Glucocorticoid;979
17.1.5.1.5;Mineralocorticoid;979
17.1.5.1.6;Vitamin D;979
17.1.6;Membrane Steroid Receptors and Signaling Pathways;979
17.1.7;Biochemistry of Thyroid Hormone Actions on Brain;980
17.1.8;Diversity of Steroid-Hormone Actions on the Brain;981
17.1.8.1;During development, steroid-hormone receptors become evident in target neurons of the brain;981
17.1.8.2;The response of neural tissue to damage involves some degree of structural plasticity, as in development;982
17.1.8.3;Activation and adaptation behaviors may be mediated by hormones;982
17.1.8.4;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
17.2.1.1;The Penfield studies;989
17.2.1.2;Amnesia patients and the role of the temporal lobe in memory;989
17.2.2;Divisions of Memory;990
17.2.2.1;Declarative memory vs. procedural memory;990
17.2.2.2;Short-term memory vs. long-term memory;990
17.2.3;Molecular Mechanisms of Learning;990
17.2.3.1;Hebb’s rule and experimental models for synaptic plasticity;990
17.2.3.2;The NMDA receptor and LTP induction;991
17.2.3.3;Molecular mechanisms underlying the early- and late-phase expressions of LTP;992
17.2.3.4;Other forms of synaptic plasticity: Long-term depression (LTD) and NMDA receptor-independent LTP;993
17.2.3.5;Doogie mice: a smart way to validate Hebb’s rule for learning and memory;994
17.2.4;Molecular Mechanisms of Memory Consolidation and Storage;996
17.2.4.1;Retrograde amnesia and post-learning consolidation by the hippocampus;996
17.2.5;Neural Population-Level Memory Traces and Their Organizing Principles;996
17.2.5.1;In search of memory’s neural code;996
17.2.5.2;Visualizing network-level real-time memory traces;999
17.2.5.3;Identification of neural cliques as real-time memory coding units;999
17.2.5.4;General-to-specific feature-encoding neural clique assemblies;999
17.2.5.5;Concept cells in the hippocampus: nest cells and Halle Berry cells;1000
17.2.5.6;Differential reactivations within episodic cell assemblies underlying selective memory consolidation;1000
17.2.5.7;The generalization function of the hippocampus;1002
17.2.5.8;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
17.3.1.1;The daily cycle of sleep and wakefulness is one of the most fundamental aspects of human biology;1008
17.3.1.2;The functions of sleep remain enigmatic;1008
17.3.1.3;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
17.3.2.1;Compared to other medical specialties, sleep disorders medicine has a very short history;1009
17.3.2.2;Understanding the neurochemical regulation of sleep is essential for advancing sleep disorders medicine;1010
17.3.3;Monoamines;1011
17.3.3.1;Serotonin, norepinephrine and histamine are major components of the ascending reticular activating system, and each of these neurotransmitters plays a unique role in…;1011
17.3.3.2;Norepinephrine promotes arousal during normal wakefulness, and augments arousal during periods of stress and in response to psychostimulant drugs;1011
17.3.3.3;Serotonin has a biphasic effect on sleep;1011
17.3.3.4;Histamine levels are greater during wakefulness than during sleep, consistent with the fastest firing rates of histamine-containing neurons occurring during wakefulness;1012
17.3.3.5;Sleep disorders and depression are linked by monoamines;1012
17.3.4;Acetylcholine;1012
17.3.4.1;Acetylcholine contributes significantly to the generation of REM sleep and wakefulness;1012
17.3.4.2;Evidence that pontine cholinergic neurotransmission promotes the generation of REM sleep comes from many studies using a wide range of approaches;1013
17.3.4.3;Acetylcholine, depression, REM sleep and pain;1013
17.3.5;Dopamine;1013
17.3.5.1;Unlike other monoaminergic neurons, dopaminergic cells do not cease firing during REM sleep;1013
17.3.5.2;Restless legs syndrome, Parkinson’s disease and sleep;1014
17.3.6;Hypocretins/Orexins;1014
17.3.6.1;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
17.3.6.2;Hypocretins promote normal wakefulness;1015
17.3.6.3;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
17.3.7.1;?-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and drugs that enhance transmission at GABAA…;1015
17.3.7.2;The effects of GABA on sleep and wakefulness vary as a function of brain region;1016
17.3.7.3;GABAergic transmission in the pontine reticular formation contributes to the regulation of sleep and wakefulness;1016
17.3.7.4;Clinical implications of GABAergic transmission for sleep;1016
17.3.7.5;Glutamate is the major excitatory neurotransmitter in the brain, yet elucidating the role of glutamate in regulating sleep and wakefulness has been challenging;1016
17.3.7.6;Effects of glutamate on sleep and wakefulness vary as a function of brain region;1017
17.3.7.7;Glutamate modulates the interaction between sleep, depression and pain;1017
17.3.8;Adenosine;1018
17.3.8.1;Adenosine is an endogenous sleep factor that mediates the homeostatic drive to sleep;1018
17.3.8.2;Adenosine inhibits wakefulness and promotes sleep via multiple mechanisms;1018
17.3.8.3;Adenosine is a link between opioid-induced sleep disruption and pain;1018
17.3.9;Conclusions and Future Directions;1019
17.3.10;References;1021
17.4;58. The Neurochemistry of Schizophrenia;1025
17.4.1;Clinical Aspects of Schizophrenia;1025
17.4.1.1;Schizophrenia is a severe, chronic disabling mental disorder;1025
17.4.1.2;Schizophrenia is characterized by three independent symptom clusters;1026
17.4.1.3;Schizophrenia is a disorder of complex genetics;1026
17.4.1.4;Current treatment of schizophrenia relies on atypical antipsychotic drugs;1026
17.4.2;Brain Imaging;1028
17.4.2.1;Brain imaging studies provide unequivocal evidence that schizophrenia is a brain disease;1028
17.4.2.2;Functional imaging studies have consistently shown corticolimbic abnormalities in schizophrenia;1028
17.4.3;Cellular and Molecular Studies;1029
17.4.3.1;The dopamine hypothesis has dominated schizophrenia research for 40 years;1029
17.4.3.2;Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia;1030
17.4.3.3;GABAergic neurons are also implicated in schizophrenia;1032
17.4.3.4;The cholinergic system has also been implicated in schizophrenia;1033
17.4.3.5;Some intracellular signal transduction molecules are reduced in schizophrenia;1033
17.4.3.6;Proteins involved in fundamental structure and function of neurons are decreased in schizophrenia;1033
17.4.3.7;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
17.5.1.1;ASDs are defined by three independent symptom clusters;1037
17.5.1.2;Autism is heterogeneous from a behavioral, neurobiological and genetic standpoint;1038
17.5.1.3;The autism field is moving towards a more dimensional and less categorical perspective;1038
17.5.1.4;Current pharmacological treatment of autism is usually effective for only certain aspects of the symptom constellation;1039
17.5.2;Genetic Studies;1039
17.5.2.1;The genetics of autism are complex, heterogenetic and, in most cases, polygenetic;1039
17.5.2.2;Roles of epistasis and emergenesis are unclear;1039
17.5.3;Neurochemical Studies;1039
17.5.3.1;Limited postmortem brain data are available and are not definitive;1039
17.5.3.2;Dopaminergic functioning appears normal;1040
17.5.3.3;Stress response systems: basal functioning is normal, but hyperreactive in autism;1040
17.5.3.4;The serotonin system: a focus on platelet hyperserotonemia and the 5-HT2 receptor;1040
17.5.3.5;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
17.6.2.1;Serotonergic system;1047
17.6.2.2;Noradrenergic system;1048
17.6.2.3;Dopaminergic system;1049
17.6.2.4;Cholinergic system;1049
17.6.2.5;Glutamatergic system;1049
17.6.2.6;GABAergic system;1049
17.6.2.7;Cortical-hypothalamic-pituitary-adrenal axis;1049
17.6.2.8;Thyroid axis;1049
17.6.2.9;Other neuropeptides;1050
17.6.2.10;Brain growth factors;1050
17.6.2.11;Substance P;1050
17.6.3;Neuroanatomical and Neuropathological Correlates of Mood Disorders;1050
17.6.3.1;Functional neuroimaging methods;1050
17.6.3.2;Stress, glucocorticoids and neuroplasticity;1051
17.6.4;Intracellular Signaling Pathways;1051
17.6.4.1;The G-protein–subunit/cyclic adenosine monophosphate (CAMP)–generating signaling pathway;1052
17.6.4.2;The protein kinase C signaling pathway;1052
17.6.4.3;Glycogen synthase kinase;1052
17.6.4.4;BDNF and Bcl-2;1054
17.6.4.5;Intracellular calcium signaling;1054
17.6.5;Anxiety Disorders;1055
17.6.6;The Neurochemistry of Fear and Anxiety;1055
17.6.6.1;Noradrenergic systems;1055
17.6.6.2;Serotonergic system;1056
17.6.6.3;GABAergic system;1056
17.6.6.3.1;CRH and stress axes;1057
17.6.6.4;Other neuropeptides;1057
17.6.6.4.1;Neuropeptide Y;1057
17.6.6.4.2;Cholecystokinin;1057
17.6.6.4.3;Substance P;1058
17.6.7;Intracellular Targets for Anxiety Disorders;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
17.7.1.1;Addiction is characterized by compulsive drug use, despite severe negative consequences;1063
17.7.1.2;Many forces may drive compulsive drug use;1063
17.7.2;Neuronal Circuitry of Addiction;1063
17.7.2.1;Natural reinforcers and drugs of abuse increase dopamine transmission;1063
17.7.2.2;Many neuronal circuits are ultimately involved in addiction;1065
17.7.3;Opiates;1066
17.7.3.1;Opiates are drugs derived from opium, including morphine and heroin;1066
17.7.3.2;There are three classical opioid receptor types;1066
17.7.3.3;Opioid receptors generally mediate neuronal inhibition;1066
17.7.3.4;Chronic opiate treatment results in complex adaptations in opioid receptor signaling;1066
17.7.3.5;Opiate addiction involves multiple neuronal systems;1066
17.7.3.6;Upregulation of the cyclic AMP (cAMP) second-messenger pathway is a well-established molecular adaptation;1067
17.7.3.7;There are two main treatments for the opiate withdrawal syndrome;1068
17.7.3.8;Endogenous opioid systems are an integral part of the reward circuitry;1068
17.7.4;Psychomotor Stimulants;1068
17.7.4.1;This drug class includes cocaine and amphetamine derivatives;1068
17.7.4.2;Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants;1068
17.7.4.3;Cocaine and amphetamines initiate neuronal adaptations by repeatedly elevating monoamine levels but ultimately affect glutamate and other transmitter systems;1069
17.7.4.4;Dopamine receptor transmission involves multiple signaling cascades and is altered in psychomotor stimulant addiction;1070
17.7.5;Cannabinoids (Marijuana);1070
17.7.5.1;Marijuana and hashish are derivatives of the cannabis sativa plant;1070
17.7.5.2;Cannabinoid effects in the CNS are mediated by the CB1 receptor;1070
17.7.5.3;Endocannabinoids are endogenous ligands for the CB1 receptor;1071
17.7.5.4;Endocannabinoids serve as retrograde messengers that regulate synaptic plasticity;1071
17.7.5.5;There are many similarities between endogenous opioid and cannabinoid systems;1073
17.7.6;Nicotine;1073
17.7.6.1;Nicotine is responsible for the highly addictive properties of tobacco products;1073
17.7.6.2;Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR);1073
17.7.6.3;The ventral tegmental area (VTA) is a critical site for nicotine action;1073
17.7.7;Ethanol, Sedatives and Anxiolytics;1074
17.7.7.1;Alcoholism is a chronic relapsing disorder;1074
17.7.7.2;Ethanol interacts directly with ligand-gated and voltage-gated ion channels;1074
17.7.7.3;Multiple neuronal systems contribute to the reinforcing effects of ethanol;1074
17.7.7.4;Pharmacotherapies for alcoholism are improving;1074
17.7.7.5;Barbiturates and benzodiazepines are used to treat anxiety;1075
17.7.8;Hallucinogens and Dissociative Drugs;1075
17.7.8.1;Hallucinogens produce an altered state of consciousness;1075
17.7.8.2;Phencyclidine (PCP) is a dissociative drug;1075
17.7.9;Addiction And Neuronal Plasticity Share Common Cellular Mechanisms;1076
17.7.9.1;Drugs of abuse “rewire” neuronal circuits by influencing synaptic plasticity;1076
17.7.9.2;Drugs of abuse have profound effects on transcription factors and gene expression;1076
17.7.9.3;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