Basic Neurochemistry (eBook)

Front Cover 1
Basic Neurochemistry: Principles of Molecular, Cellular and Medical Neurobiology 4
Copyright Page 5
Contents 8
List of Boxes 10
Sections 14
Contributors 16
Eighth Edition Acknowledgments and History 22
Preface to the Eighth Edition 24
I. CELLULAR NEUROCHEMISTRY AND NEURAL MEMBRANES 26
1. Cell Biology of the Nervous System 28
Overview 29
Cellular Neuroscience is the Foundation of Modern Neuroscience 29
Diverse cell types comprising the nervous system interact to create a functioning brain 29
Neurons: Common Elements and Diversity 29
The classic image of a neuron includes a perikaryon, multiple dendrites and an axon 29
Although neurons share common elements with other cells, each component has specialized features 31
The axon compartment comprises the axon hillock, initial segment, shaft and terminal arbor 34
Dendrites are the afferent components of neurons 34
The synapse is a specialized junctional complex by which axons and dendrites emerging from different neurons intercommunicate 35
Macroglia: More than Meets the Eye 36
Virtually nothing can enter or leave the central nervous system parenchyma without passing through an astrocytic interphase 36
Oligodendrocytes are myelin-producing cells in the central nervous system 38
The schwann cell is the myelin-producing cell of the peripheral nervous system 38
Microglia 40
The microglial cell plays a role in phagocytosis and inflammatory responses 40
Ependymal cells line the brain ventricles and the spinal cord central canal 41
Blood–Brain Barriers and the Nervous System 41
Homeostasis of the central nervous system (CNS) is vital to the preservation of neuronal function 41
The BBB and BCSFB serve a number of key functions critical for brain function 42
Evolution of the blood–brain barrier concept 43
The Neurovascular Unit Includes Multiple Components 43
The lumen of the cerebral capillaries that penetrate and course through the brain tissue are enclosed by BECs interconnected by TJ 43
The basement membrane (BM)/basal lamina is a vital component of the BBB 44
Astrocytes contribute to the maintenance of the BBB 44
Pericytes at the BBB are more prevalent than in other capillary types 44
Brain endothelial cells restrict the transport of many substances while permitting essential molecules access to the brain 44
There are multiple transporters and transport processes for bidirectional transport at the BBB 46
Lipid solubility is a key factor in determining the permeability of a substance through the BBB by passive diffusion 46
The BBB expresses solute carriers to allow access to the brain of molecules essential for metabolism 47
Receptor-mediated transcytosis (RMT) is the primary route of transport for some essential peptides and signaling molecules 47
ATP-binding cassette transporters (ABC) on luminal membranes of the BBB restrict brain entry of many molecules 47
During development, immune-competent microglia develop and reside in the brain tissue 48
There is increasing evidence of BBB dysfunction, either as a cause or consequence, in the pathogenesis of many diseases affecting the CNS 48
The presence of an intact BBB affects the success of potentially beneficial therapies for many CNS disorders 48
Acknowledgements 48
References 50
2. Cell Membrane Structures and Functions 51
Phospholipid Bilayers 51
Cells are bounded by proteins arrayed in lipid bilayers 51
Amphipathic molecules can form bilayered lamellar structures spontaneously if they have an appropriate geometry 52
Membrane Proteins 53
Membrane integral proteins have transmembrane domains that insert directly into lipid bilayers 53
Many transmembrane proteins that mediate intracellular signaling form complexes with both intra- and extracellular proteins 54
Membrane associations can occur by selective protein binding to lipid head groups 54
Biological Membranes 54
The fluidity of lipid bilayers permits dynamic interactions among membrane proteins 54
The lipid compositions of plasma membranes, endoplasmic reticulum and golgi membranes are distinct 56
Cholesterol transport and regulation in the central nervous system is isolated from that of peripheral tissues 56
In adult brain most cholesterol synthesis occurs in astrocytes 56
The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling 57
The structure and roles of membrane microdomains (lipid rafts) in cell membranes are under intensive study but many aspects are still unresolved 58
Mechanical functions of cells require interactions between integral membrane proteins and the cytoskeleton 59
The spectrin–ankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membrane… 59
Interaction of rafts with the cytoskeleton is suggested by the results of video microscopy 60
References 63
3. Membrane Transport 65
Introduction 66
Primary Active Transport (P-Type) Pumps 66
Na,K-Adenosinetriphosphatase (Na,K-ATPase) 67
The reaction mechanism of Na,K-ATPase illustrates the mechanism of P-type pumps 67
Molecular structures of the catalytic subunits in the P-type transporters are similar 68
The active Na,K-ATPase is a heterodimer consisting of a catalytic a subunit and an accessory ß subunit 68
The a-subunit isoforms are expressed in a cell- and tissue-specific manner 68
The ß subunits are monotopic glycoproteins and exhibit some characteristics of cell adhesion molecules 68
The Na pump has associated . subunits 69
A major fraction of cerebral energy production is consumed by the Na,K pump 70
Na,K-ATPase Expression patterns change with development, aging and dementia 70
Na,K pump content in plasmalemma is regulated by its rapid endocytic–exocytic cycling 70
The distributions of a-subunit isoforms provide clues to their different physiological functions 70
Regulatory factors direct the trafficking of Na,K-ATPase during its synthesis 71
The Na,K-ATPase/Src complex functions as a signal receptor for cardiotonic steroids (CTS) 71
Domain-specific interactions make the Na,K-ATPase an important scaffold in forming signaling microdomains 73
Ca Adenosinetriphosphatases and Na,Ca Antiporters 73
The Primary Plasma Membrane Ca Transporter (PMCA) 73
PMCA is a plasmalemma P-type pump with high affinity for Ca2+ 73
Smooth Endoplasmic Reticulum Calcium Pumps (SERCA) 73
SERCA, another P-type Ca pump, was first identified in sarcoplasmic reticulum 73
High-resolution structural data exist for the SERCA1a Ca pump 73
Other P-Type Transporters 75
P-type copper transporters are important for neural function 75
V0V1 Proton Pumps 75
The V0V1-ATPase pumps protons into golgi-derived organelles 75
ATP-Binding Cassettes 75
The ABC transporters are products of one of the largest known gene superfamilies 75
The Three-dimensional structures of several ABC transporters from prokaryotes have been determined 75
ABCA1 translocates cholesterol and phospholipids outward across the plasma membrane 76
The multidrug-resistance proteins (MDR) can ‘flip’ amphipathic molecules 77
Secondary Active Transport 77
Brain capillary endothelial cells and some neurons express a Na-dependent D-glucose symporter 77
Neurotransmitter sodium symporters (NSS) effect the recovery of neurotransmitters from synaptic clefts 77
There are two distinct subfamilies of neurotransmitter sodium symporters 77
The SLC6 subfamily of symporters for amino acid transmitters and biogenic amines is characterized by a number of shared structural features 77
SLC1 proteins encompass glutamate symporters as well as some amino- and carboxylic-acid transporters expressed in bacteria 78
The glutamate symporters in brain are coded by five different but closely related genes, SLC1A1–4 and SLC1A6 78
Failure of regulation of glutamate concentration in its synaptic, extracellular and cytosol compartments leads to critical pathology 79
Choline transporter: termination of the synaptic action of acetylcholine is unique among neurotransmitters 79
Packaging neurotransmitters into presynaptic vesicles is mediated by proton-coupled antiporters 79
General Physiology of Neurotransmitter Uptake and Storage 80
The Cation Antiporters 80
Na,Ca exchangers are important for rapidly lowering high pulses of cytoplasmic Ca2+ 80
Na,K-ATPase a subunits are coordinated with Na,Ca antiporters and Ca pumps 80
The overall mechanism for regulation of cytosolic Ca2+ is complex 80
The Anion Antiporters 81
Anion antiporters comprising the SLC8 gene family all transport bicarbonate 81
Intracellular pH in brain is regulated by Na,H antiporters, anion antiporters and Na,HCO3 symporters 81
Facilitated Diffusion: Aquaporins and Diffusion of Water 81
Simple diffusion of polar water molecules through hydrophobic lipid bilayers is slow 81
Crystallographic and architectural data are available for AQP1 and AQP4 82
The aquaporins found in brain are AQP1, 4 and 9 82
In astrocytic perivascular endfeet membranes, AQP4 is anchored to the dystrophin complex of proteins 82
AQP4 exists in astrocyte membranes and is coordinated with other proteins with which its function is integrated 82
Rapid diffusion of K+ and H2O from Neuronal extracellular space by astroglia is critical to brain function 83
Short-term regulation of AQP4 may result from phosphorylation of either of two serine residues 83
Facilitated Diffusion of Glucose and Myoinositol 83
Facilitated diffusion of glucose across the blood–brain barrier is catalyzed by GLUT-1, -2 and -3 83
HMIT is an H-coupled myoinositol symporter 84
References 85
4. Electrical Excitability and Ion Channels 88
Membrane Potentials and Electrical Signals in Excitable Cells 89
Excitable cells have a negative membrane potential 89
Real cells are not at equilibrium 90
Transport systems may also produce membrane potentials 90
Electrical signals recorded from cells are of two types: stereotyped action potentials and a variety of slow potentials 90
Action Potentials in Electrically Excitable Cells 91
During excitation, ion channels open and close and a few ions flow 91
Gating mechanisms for Na+ and K+ channels in the axolemma are voltage dependent 91
The action potential is propagated by local spread of depolarization 92
Membranes at nodes of ranvier have high concentrations of Na+ channels 92
Functional Properties of Voltage-Gated Ion Channels 92
Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane 92
Voltage-dependent gating requires voltage-dependent conformational changes in the protein component(s) of ion channels 93
Pharmacological agents acting on ion channels help define their functions 93
The Voltage-Gated Ion Channel Superfamily 94
Na+ channels were identified by neurotoxin labeling and their primary structures were established by cDNA cloning 94
Ca2+ channels have a structure similar to Na+ channels 96
Voltage-gated K+ channels were identified by genetic means 96
Inwardly rectifying K+ channels were cloned by expression methods 96
The Molecular Basis for Ion Channel Function 96
Much is known about the structural determinants of the ion selectivity filter and pore 96
Voltage-dependent activation requires moving charges 99
The fast inactivation gate is on the inside 99
Ion Channel Diversity 100
Na+ channels are primarily a single family 100
Three subfamilies of Ca2+ channels serve distinct functions 100
There are many families of K+ channels 101
More ion channels are related to the NaV, CaV and KV families 101
There are many other kinds of ion channels with different structural backbones and topologies 102
Ion channels are the targets for mutations that cause genetic diseases 102
Acknowledgments 102
References 104
5. Lipids 106
Introduction 106
Properties of Brain Lipids 107
Lipids have multiple functions in brain 107
Membrane lipids are amphipathic molecules 107
The hydrophobic components of many lipids consist of either isoprenoids or fatty acids and their derivatives 107
Isoprenoids have the unit structure of a five-carbon branched chain 107
Brain fatty acids are long-chain carboxylic acids that may contain one or more double bonds 107
Complex Lipids 108
Glycerolipids are derivatives of glycerol and fatty acids 108
In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone 110
Analysis of Brain Lipids 114
Chromatography and mass spectrometry are employed to analyze and classify brain lipids 114
Brain Lipid Biosynthesis 115
Acetyl coenzyme A is the precursor of both cholesterol and fatty acids 115
Phosphatidic acid is the precursor of all glycerolipids 119
Sphingolipids are biosynthesized by adding head groups to the ceramide moiety 121
Genes for Enzymes Catalyzing Synthesis and Degradation of Lipids 121
Lipids in the Cellular Milieu 123
Lipids are transported between membranes 123
Membrane lipids may be asymmetrically oriented 123
Some proteins are bound to membranes by covalently linked lipids 123
Lipids have multiple roles in cells 124
Summary 124
Acknowledgments 124
References 124
6. The Cytoskeleton of Neurons and Glia 126
Introduction 126
Molecular Components of the Neuronal Cytoskeleton 127
Along with the nucleus and mitochondria, the cytoskeleton is one of several biological structures that define eukaryotic cells 127
Microtubules act as both dynamic structural elements and tracks for organelle traffic 127
Neuronal and glial intermediate filaments provide support for neuronal and glial morphologies 131
Actin microfilaments and the membrane cytoskeleton play critical roles in neuronal growth and secretion 133
Ultrastructure and Molecular Organization of Neurons and Glia 135
A dynamic neuronal cytoskeleton provides for specialized functions in different regions of the neuron 135
Both the composition and organization of cytoskeletal elements in axons and dendrites become specialized early in differentiation 136
Cytoskeletal Structures in the Neuron Have Complementary Distributions and Functions 137
Microfilament and microtubule dynamics underlie growth cone motility and function 137
The axonal cytoskeleton may be influenced by glia 137
Levels of cytoskeletal protein expression change after injury and during regeneration 139
Alterations in the cytoskeleton are frequent hallmarks of neuropathology 139
Phosphorylation of cytoskeletal proteins is involved both in normal function and in neuropathology 141
Summary 141
References 141
7. Intracellular Trafficking 144
Introduction 145
General Mechanisms of Intracellular Membrane Trafficking in Mammalian Cells Include Both Universal and Highly Specialized Processes 145
Fundamentals of Membrane Trafficking are Based on a set of Common Principles 146
Most transport vesicles bud off as coated vesicles, with a unique set of proteins decorating their cytosolic surface 146
GTP-binding proteins, such as small monomeric GTPases and heterotrimeric GTPases (G proteins) facilitate membrane transport 147
Dynamins are involved in pinching off of many vesicles and membrane-bounded organelles 148
Removal of coat proteins is catalyzed by specific protein chaperones 149
SNARE proteins and rabs control recognition of specific target membranes 150
Unloading of the transport vesicle cargo to the target membrane occurs by membrane fusion 150
The biosynthetic Secretory Pathway Includes Synthetic, Processing, Targeting and Secretory Steps 151
Historically, endoplasmic reticulum has been classified as rough or smooth, based on the presence (RER) or absence (SER) of membraneassociated polysomes 151
Biosynthetic and secretory cargo leaving the ER is packaged in COPII-coated vesicles for delivery to the Golgi complex 152
The Golgi apparatus is a highly polarized organelle consisting of a series of flattened cisternae, usually located near the nucleus and the centrosome 154
Processing of proteins in the Golgi complex includes sorting and glycosylation of membrane proteins and secretory proteins 154
Proteins and lipids move through Golgi cisternae from the cis to the trans direction 155
Plasma membrane proteins are sorted to their final destinations at the trans-Golgi network 156
Lysosomal proteins are also sorted and targeted in the trans-Golgi network 157
Several intracellular trafficking pathways converge at lysosomes 157
Both constitutive and regulated neuroendocrine secretion pathways exist in cells of the nervous system 157
The constitutive secretory pathway is also known as the default pathway because it occurs in the absence of a triggering signal 159
Secretory cells, including neurons, possess a specialized regulated secretory pathway 159
Secretory vesicle biogenesis requires completion of a characteristic sequence of steps before vesicles are competent for secretion 159
The Endocytic Pathway Plays Multiple Roles in Cells of the Nervous System 160
Endocytosis for degradation of macromolecules and uptake of nutrients involves phagocytosis, pinocytosis and autophagy 160
Retrieval of membrane components in the secretory pathway through receptor-mediated endocytosis (RME) is a clathrin-coat-dependent process 162
Synaptic Vesicle Trafficking is a Specialized Form of Regulated Secretion and Recycling Optimized for Speed and Efficiency 164
The organization of the presynaptic terminal is one important element for optimization of secretion and recycling 164
In a simplistic model, the exocytosis step of neurotransmission takes place in at least three major different steps 164
Many years have passed since the concept of synaptic vesicle recycling was introduced in the early 1970s, but details… 167
Acknowledgments 169
References 169
8. Axonal Transport 171
Introduction 171
Neuronal Organelles in Motion 172
Discovery and Development of the Concept of Fast and Slow Components of Axonal Transport 172
The size and extent of many neurons presents a special set of challenges 172
Fast and slow components of axonal transport differ in both their constituents and their rates 173
Features of fast axonal transport demonstrated by biochemical and pharmacological approaches are apparent from video images 176
Fast Axonal Transport 176
Newly synthesized membrane and secretory proteins destined for the axon travel by fast anterograde transport 176
Passage through the golgi apparatus is obligatory for most proteins destined for fast axonal transport 177
Anterograde fast axonal transport moves synaptic vesicles, axolemmal precursors, and mitochondria down the axon 178
Retrograde transport returns trophic factors, exogenous material, and old membrane constituents to the cell body 178
Molecular sorting mechanisms ensure delivery of proteins to discrete membrane compartments 179
Slow Axonal Transport 180
Cytoplasmic and cytoskeletal elements move coherently at slow transport rates 180
Axonal growth and regeneration are limited by rates of slow axonal transport 180
Properties of slow axonal transport suggest molecular mechanisms 181
Molecular Motors: Kinesin, Dynein and Myosin 181
The characteristic biochemical properties of different molecular motors aided in their identification 182
Kinesins mediate anterograde fast axonal transport in a variety of cell types 182
Mechanisms underlying attachment of motors to transported MBOs remain elusive 183
Multiple members of the kinesin superfamily are expressed in the nervous system 183
Cytoplasmic dyneins have multiple roles in the neuron 184
Different classes of myosin are important for neuronal function 185
Matching motors to physiological functions may be difficult 185
AXONAL Transport and Neuropathology 186
Acknowledgments 187
References 187
9. Cell Adhesion Molecules 190
Overview 190
Cell adhesion molecules comprise several ‘superfamilies’ 191
Immunoglobulin Superfamily 191
The immunoglobulin (Ig)-like domain is a typical feature of proteins belonging to the immunoglobulin superfamily 191
Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) represent a diverse group of proteins 191
IgCAMs signal to the cytoplasm 193
Cadherins 194
The extracellular cadherin (EC) repeat is a typical feature of cadherins 194
The type I (‘classic’) cadherins are homophilic cell adhesion molecules 194
Cadherins are involved in multiple processes in the nervous system 194
Integrins 195
Integrins are the major cell surface receptors responsible for cell adhesion to extracellular matrix (ECM) proteins 195
Integrins signal in an inside-out and outside-in fashion 197
Integrins regulate myelination 198
Cooperation and Crosstalk between Cell Adhesion Molecules 200
Various cell adhesion molecules cooperatively regulate the formation of interneuronal synapses in the CNS 200
Integrin-cadherin cross-talk regulates neurite outgrowth 202
Summary 203
References 203
10. Myelin Structure and Biochemistry 205
The Myelin Sheath 205
Myelin facilitates conduction 205
Myelin has a characteristic ultrastructure 206
Nodes of Ranvier 207
Myelin is an extension of a cell membrane 209
Myelin affects axonal structure 210
Characteristic Composition of Myelin 210
The composition of myelin is well characterized because it can be isolated in high yield and purity by subcellular fractionation 210
Central nervous system myelin is enriched in certain lipids 211
Peripheral and central nervous system myelin lipids are qualitatively similar 212
Central nervous system myelin contains some unique proteins 213
Proteolipid protein 213
Myelin basic proteins 214
2':3'-cyclic nucleotide 3'-phosphodiesterase 215
Myelin-associated glycoprotein (MAG) and other glycoproteins of CNS myelin 216
Peripheral myelin also contains unique proteins 217
P0 glycoprotein 217
Peripheral myelin protein-22 217
P2 protein 218
Some classically defined myelin proteins are common to both CNS and PNS myelin 218
Myelin basic protein 218
Myelin-associated glycoprotein 218
Myelin sheaths contain other proteins, some of which have only recently been established as myelin related 219
Tetraspan proteins 219
Nodal, paranodal, and juxtaparanodal proteins 220
Enzymes associated with myelin 220
Neurotransmitter receptors associated with myelin 222
Other myelin-related proteins 222
Acknowledgments 222
References 222
11. Energy Metabolism of the Brain 225
Introduction 226
Processes related to signaling require a larger proportion of energy than do ‘basic’ cellular functions 226
Function-derived signals arising from metabolism are used for brain imaging 227
Major cell types and their subcellular structures have different energetic requirements and metabolic capabilities 228
Substrates for Cerebral Energy Metabolism 228
Energy-yielding substrates enter the brain from the blood through the blood–brain barrier 228
Endothelial cells of the blood–brain barrier and brain cells have specific transporters for the uptake of glucose and monocarboxylic acids 228
Blood–brain barrier transport can be altered under pathological conditions 229
Age and Development Influence Cerebral Energy Metabolism 229
The transporters and pathways of metabolism change during development 229
Cerebral metabolic rate increases during early development 230
Cerebral metabolic rate declines from developmental levels and plateaus after maturation 230
Fueling Brain: Supply–Demand Relationships and Cerebral Metabolic Rate 230
Both excitatory and inhibitory neuronal signals utilize energy derived from metabolism 230
Continuous cerebral circulation is required to sustain brain function 231
Glucose is the main obligatory substrate for energy metabolism in adult brain 231
Metabolism in the Brain is Highly Compartmentalized 232
Glucose has numerous metabolic fates in brain 232
Glycolysis: Conversion of Glucose to Pyruvate 232
Regulation of brain hexokinase 232
Phosphofructokinase is the major regulator of brain glycolysis 233
Glycolysis produces ATP, pyruvate for mitochondrial metabolism, and precursors for amino acids and complex carbohydrates 233
Glycogen is Actively Synthesized and Degraded in Astrocytes 234
The steady-state concentration of glycogen is regulated by coordination of separate degradative and synthetic enzymatic processes 235
The Pentose Phosphate Shunt has Essential Roles in Brain 235
The Malate–Aspartate Shuttle has a key Role in Brain Metabolism 235
The malate–aspartate shuttle is the most important pathway for transferring reducing equivalents from the cytosol to the… 235
The malate–aspartate shuttle has a role in linking metabolic pathways in brain 236
There is Active Metabolism of Lactate in Brain 236
Lactate–pyruvate interconversion 236
Lactate is formed in brain under many conditions 236
Compartmentation of the pyruvate–lactate pool is unexpectedly complex 239
Lactate can serve as fuel for brain cells under various conditions 239
The astrocyte–neuron lactate shuttle is controversial 240
Major Functions of the Tricarboxylic Acid (TCA) Cycle: Pyruvate Oxidation to CO2, NADH/FADH2 Formation for ATP Generation… 240
The TCA (citric acid) cycle is multifunctional 240
The pyruvate dehydrogenase complex plays a key role in regulating oxidation of glucose 242
TCA cycle rate 242
Malate dehydrogenase is one of several enzymes in the TCA cycle present in both the cytoplasm and mitochondria 242
The electron transport chain produces ATP 242
ATP production in brain is highly regulated 242
Phosphocreatine has a role in maintaining ATP levels in brain 243
Pyruvate carboxylation in astrocytes is the major anaplerotic pathway in brain 243
Citrate is a multifunctional compound predominantly synthesized and released by astrocytes 243
Acetyl-coenzyme A formed from glucose is the precursor for acetylcholine in neurons 243
Mitochondrial Heterogeneity: Differential Distribution of Many TCA Cycle Enzymes and Components of Oxidative Phosphorylation… 244
Mitochondria are distributed with varying densities throughout the central nervous system, with the more vascular parts… 244
Mitochondrial heterogeneity leads to multiple simultaneous TCA cycles in astrocytes and neurons 244
Partial TCA cycles can provide energy in brain 244
Other substrates (e.g., glutamate, glutamine, lactate, fatty acids, and ketone bodies) can provide energy for brain cells 244
Glutamate–Glutamine Metabolism is Linked to Energy Metabolism 245
Transporters are required to carry glutamate and other amino acids across the mitochondrial membrane 245
Metabolism of both glutamate and glutamine is linked to TCA cycle activity 245
Glutamate participates in a number of metabolic pathways, and metabolism of glutamate and glutamine is compartmentalized 245
The glutamate–glutamine cycle 246
A specialized glutamate–glutamine cycle operates in Gabaergic neurons and surrounding astrocytes 247
Several shuttles act to transfer nitrogen in brain 247
Metabolic Studies in Brain: Imaging and Spectroscopy 247
Global assays of whole brain 247
Local rates of glucose and oxygen utilization, functional brain imaging, redox state, and metabolic pathway analysis 247
Carbon-13 nuclear magnetic resonance spectroscopy (NMR or MRS) for studying brain metabolism 249
Cultured neurons and astrocytes are useful for studying subcellular compartmentation and identifying pathways of metabolism 250
Metabolic assays in brain slices, axons, synaptosomes and isolated mitochondria 251
Concentrations of compounds in brain and regulation of metabolism in the intact brain 251
Relation of Energy Metabolism to Pathological Conditions in the Brain 251
Acknowledgments 251
References 251
II. INTERCELLULAR SIGNALING 258
12. Synaptic Transmission and Cellular Signaling: An Overview 260
Synaptic Transmission 260
Chemical transmission between nerve cells involves multiple steps 260
Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cells 262
A variety of methods have been developed to study exocytosis 263
The neuromuscular junction is a well-defined structure that mediates the release and postsynaptic effects of acetylcholine 263
Quantal analysis defines the mechanism of release as exocytosis 264
Ca2+ is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis 264
Presynaptic events during synaptic transmission are rapid, dynamic and interconnected 266
Because fast synaptic transmission involves recycling vesicles, the neurotransmitter must be replenished locally 270
Discrete steps in the regulated secretory pathway can be defined in neuroendocrine cells 270
Cellular Signaling Mechanisms 270
Background 270
Three phases of receptor-mediated signaling can be identified 271
Several major molecular mechanisms that link agonist occupancy of cell-surface receptors to functional responses have been identified 271
First group 271
Second group 273
Third group 273
Fourth group 273
Cross-talk can occur between intracellular signaling pathways 274
Signaling molecules can activate gene transcription 274
Nitric oxide acts as an intercellular signaling molecule in the central nervous system 274
Astrocytes also play a pivotal role in signaling events at the synapse 281
Acknowledgments 281
References 281
13. Acetylcholine 283
Introduction 284
Synthesis, Storage and Release of Acetylcholine: Distribution of Cholinergic Pathways 285
Acetylcholine formation is catalyzed by choline acetyltransferase 285
Choline is accumulated into synaptic terminals via a specific high-affinity transporter 285
ACh is packaged into vesicles by a specific transporter and is released from neurons in a Ca2+-dependent manner 286
Cholinergic neurons are widely distributed within the CNS 287
Enzymatic Breakdown of Acetylcholine 287
Acetylcholinesterase and the removal of ACh 287
Molecular forms of AChE 287
AChE is encoded by a single gene that is subject to alternative splicing 288
AChE catalysis: mechanism of a nearly perfect enzyme 288
The active site is at the bottom of a narrow gorge in the AChE protein 289
Inhibitors of AChE have toxicological, agrochemical and clinical significance 290
Does AChE have other functions? 291
Nicotinic Cholinergic Receptors 291
The nicotinic receptor was the first receptor to be characterized biochemically 291
nAChRs are pentameric ligand-gated ion channels 292
Agonists bind at the interface between adjacent subunits 293
The nAChR is the prototypical member of the cys-loop family of ligand-gated ion channel receptors 294
The nAChR ion channel 294
The prolonged presence of agonist leads to desensitization 294
Neuronal nAChRs form a family of related receptors 294
The permutations of subunits forming nAChRs create more diversity 296
Neuronal nAChRs modulate brain function 296
Transgenic mice help to reveal the physiological roles and clinical implications of nAChRs 296
Neuronal nAChRs are also present in non-neuronal cells 297
nAChRs and disease 297
nAChRs as therapeutic targets 298
Muscarinic Cholinergic Receptors 299
Some effects of ACh can be mimicked by the alkaloid muscarine 299
Muscarinic cholinergic responses are mediated by G-protein–coupled receptors 299
Pharmacological studies were the first to indicate the presence of multiple mAChR subtypes 299
Molecular cloning of the mAChR reveals five subtypes 300
Muscarinic receptor subtypes couple to distinct G-proteins and activate different effector mechanisms 301
Muscarinic receptor subtypes are not uniformly distributed throughout the CNS and are present at different subcellular locations 302
Muscarinic receptors in the CNS have been implicated in a number of neuropsychiatric disorders 302
Transgenic mice permit an assessment of the physiological roles of individual subtypes in vivo 302
Pharmacological therapies are used to treat cholinergic disorders 303
References 305
14. Catecholamines 308
Overview of Catecholamines 308
Catecholamines belong to the group of transmitters called monoamines 308
Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis 309
Aromatic amino acid decarboxylase (AAAD), also called DOPA decarboxylase, catalyzes the conversion of L-DOPA to dopamine 310
In noradrenergic and adrenergic neurons, dopamine is further converted to norepinephrine by Dopamine-ß-hydroxylase (DBH) 311
In select neurons and adrenal medulla, norepinephrine is metabolized to epinephrine by phenylethanolamine-n-methyltransferase (PNMT) 313
Catecholamines are stored in small, clear synaptic vesicles or large, dense-core granules 313
Catecholamines are released from synaptic vesicles and the vesicles recycle 313
The physiological actions of catecholamines are terminated by reuptake into the neuron, catabolism and diffusion 313
Diffusion also plays an important role in the inactivation of catecholamines 315
Catecholamines are primarily metabolized by monoamine oxidase and catechol-o-methyltransferase 315
Monoamine oxidase (MAO) 315
Catechol-O-methyltransferase (COMT) 316
Dopamine metabolites 317
Norepinephrine metabolism 317
Neuroanatomy 317
Catecholamines elicit their effects by binding to cell-surface receptors 318
Adrenergic Receptors 320
All adrenergic receptors are GPCRs 320
Agonist-Induced Downregulation 322
Repeated Antagonist Treatment 322
References 323
15. Serotonin 325
Serotonin, the Neurotransmitter 326
The indolealkylamine 5-hydroxytryptamine (5-HT serotonin) was initially identified because of its effects on smooth muscle
Understanding the neuroanatomical organization of serotonergic neurons provides insight into the functions of this neurotransmitter… 326
The amino acid L-tryptophan serves as the precursor for the synthesis of 5-HT 329
The synthesis of 5-HT can increase markedly under conditions requiring more neurotransmitter 331
As with other biogenic amine transmitters, 5-HT is stored primarily in vesicles and is released by an exocytotic mechanism 331
The activity of 5-HT in the synapse is terminated primarily by its reuptake into serotonergic terminals 333
Acute and chronic regulation of SERT function provides mechanisms for altering synaptic 5-HT concentrations and neurotransmission 334
The primary catabolic pathway for 5-HT is oxidative deamination by the enzyme monoamine oxidase 335
In addition to classical synaptic transmission, 5-HT may relay information by volume transmission or paracrine neurotransmission 336
5-HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state… 336
5-HT modulates neuroendocrine function 337
5-HT modulates circadian rhythmicity 337
5-HT modulates feeding behavior and food intake 337
Serotonin Receptors 338
Pharmacological and physiological studies have contributed to the definition of the many receptor subtypes for serotonin 338
The application of techniques used in molecular biology to the study of 5-HT receptors led to the rapid discovery of addition… 339
The 5-HT1 receptor family is composed of the 5-HT1A, 5-HT1B, 5-HT1D, 5-ht1E and 5-HT1F receptors 339
The 5-HT1A receptor 339
The 5-HT1B and 5-HT1D receptor subtypes 341
The 5-ht1E receptor 342
The 5-HT1F receptor 342
The 5-HT2 receptor family is composed of the 5-HT2A, 5-HT2B and 5HT2C receptors 342
5-HT2A receptors 342
The 5-HT2B receptor 343
The 5-HT2C receptor 343
Unlike the other subtypes of receptor for 5-HT, the 5-HT3 receptor is a ligand-gated ion channel 343
The 5-HT3 receptor 343
The 5-HT4, 5-HT6 and 5-HT7 receptors are coupled to the stimulation of adenylyl cyclase 344
The 5-HT4 receptor 344
The 5-HT6 receptor 345
The 5-HT7 receptor 345
The 5-ht5 receptor and the 5-ht1P receptor are orphan receptors 345
References 346
16. Histamine 348
Introduction 349
Histamine: The Molecule and the Messenger 349
Histamine is a mediator of several physiological and pathological processes within and outside of the nervous system 349
The chemical structure of histamine has similarities to the structures of other biogenic amines, but important differences also exist 349
Histaminergic Cells of the Central Nervous System: Anatomy and Morphology 349
The brain stores and releases histamine from more than one type of cell 349
Several functions for brain and dural mast cells are investigated 349
Histaminergic fibers originate from the tuberomamillary (TM) region of the posterior hypothalamus 349
Histaminergic neurons have morphological and membrane properties that are similar to those of neurons storing other biogenic amines 350
Histaminergic fibers project widely to most regions of the central nervous system 350
Dynamics of Histamine in the Brain 352
Specific enzymes control histamine synthesis and breakdown 352
Several forms of histidine decarboxylase (HDC) may derive from a single gene 353
Histamine synthesis in the brain is controlled by the availability of l-histidine and the activity of HDC 353
Histamine is stored within and released from neurons 353
In the vertebrate brain, histamine metabolism occurs predominantly by methylation 353
Neuronal histamine can be methylated outside of histaminergic nerve terminals 353
A polymorphism in human HMT (Thr105Ile) may be an important regulatory factor in some human disorders 354
The activity of histaminergic neurons is regulated by H3 autoreceptors and by other transmitter receptors 354
Molecular Sites of Histamine Action 354
Histamine acts on four G-protein–coupled receptors (GPCRs), three of which are clearly important in the brain 354
H1 receptors are intronless GPCRs linked to Gq and calcium mobilization 354
H1-linked intracellular messengers 355
H2 receptors are intronless GPCRs linked to Gs and cyclic AMP synthesis 356
H2-linked intracellular messengers 356
H3 receptors are a family of GPCRs produced by gene splicing and linked to Gi/o 356
H3 receptor gene splicing 358
H3-linked intracellular messengers 358
Constitutive H3 receptor activity 359
H4 receptors are very similar to H3 receptors in gene structure and signal transduction, but show limited expression in the brain 359
H4-linked intracellular messengers 360
Histamine can modify ionotropic transmission 360
Histamine Actions on the Nervous System 360
Histamine in the brain may act as both a neuromodulator and a classical transmitter 360
Histaminergic neurons are mutually connected with other neurotransmitter systems 360
Histamine functions in the nervous system 361
Histamine may contribute to nervous system diseases or disorders 362
Significance of Brain Histamine for Drug Action 362
Many clinically available drugs that modify sleep–wake cycles and appetite act through the histaminergic system 362
Drugs that modify pain perception act in part through the histaminergic system 362
The H3 receptor is an attractive target for the treatment of several CNS diseases 362
References 364
17. Glutamate and Glutamate Receptors 367
The Amino Acid Glutamate is the Major Excitatory Neurotransmitter in the Brain 368
Brain Glutamate is Derived from Blood-Borne Glucose and Amino Acids that Cross the Blood–Brain Barrier 368
Glutamine is an Important Immediate Precursor for Glutamate: The Glutamine Cycle 369
Release of glutamate from nerve endings leads to loss of a-ketoglutarate from the tricarboxylic acid cycle 370
Synaptic Vesicles Accumulate Transmitter Glutamate by Vesicular Glutamate Transporters 371
Zinc is present together with glutamate in some glutamatergic vesicles 371
Is Aspartate a Neurotransmitter? 371
Long-Term Potentiation or Depression of Glutamatergic Synapses May Underlie Learning 371
The Neuronal Pathways of the Hippocampus are Essential Structures for Memory Formation 372
Ionotropic and Metabotropic Glutamate Receptors are Principal Proteins at the Postsynaptic Density 372
Three Classes of Ionotropic Glutamate Receptors are Identified 372
Seven functional families of ionotropic glutamate receptor subunits can be defined by structural homologies 373
AMPA and kainate receptors are both blocked by quinoxalinediones but have different desensitization pharmacologies 375
N-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites 375
The transmembrane topology of glutamate receptors differs from that of nicotinic receptors 379
Structure of the agonist-binding site has been analyzed 379
Genetic regulation via splice variants and RNA editing further increases receptor heterogeneity: the flip/flop versions… 379
The permeation pathways of all ionotropic glutamate receptors are similar, but vive la difference 381
Glutamate Produces Excitatory Postsynaptic Potentials 381
Genetic knockouts provide clues to ionotropic receptor functions 383
Metabotropic Glutamate Receptors Modulate Synaptic Transmission 383
Eight metabotropic glutamate receptors (mGlu receptors) have been identified that embody three functional classes 383
mGlu receptors are linked to diverse cytoplasmic signaling enzymes 383
Postsynaptic mGlu receptor activation modulates ion channel activity 383
Presynaptic mGlu receptor activation can lead to presynaptic inhibition 384
Genetic knockouts provide clues to mGlu receptor functions 384
Glutamate Receptors Differ in their Postsynaptic Distribution 384
Proteins of the Postsynaptic Density Mediate Intracellular Effects of Glutamate Receptor Activation 385
A major scaffolding protein of the PSD is PSD95 385
Small GTP-binding proteins (GTPases) mediate changes in gene expression upon NMDA receptor activation 386
Dendritic Spines are Motile, Changing their Shape and Size in Response to Synaptic Activity within Minutes 386
Sodium-Dependent Symporters in the Plasma Membranes Clear Glutamate from the Extracellular Space 386
Sodium-Dependent Glutamine Transporters in Plasma Membranes Mediate the Transfer of Glutamine from Astrocytes to Neurons 387
Excessive Glutamate Receptor Activation may Mediate Certain Neurological Disorders 388
Glutamate and its analogs can be neurotoxins and cause excitotoxicity 388
Some dietary neurotoxins may cause excessive glutamate receptor activation and cell death 388
Abnormal activation of glutamate receptors in disorders of the central nervous system 388
References 390
18. GABA 392
Introduction 392
GABA Synthesis, Release and Uptake 393
GABA is formed in vivo by a metabolic pathway referred to as the GABA shunt 393
GABA Receptor Physiology and Pharmacology 393
GABA receptors have been identified electrophysiologically and pharmacologically in all regions of the brain 393
Structure and Function of GABA Receptors 394
GABAB receptors are coupled to G proteins and a variety of effectors 394
GABAB receptors are heterodimers 394
GABAA receptors are chloride channels and members of a superfamily of ligand-gated ion channel receptors 395
A family of pentameric GABAA-receptor protein subtypes exists these vary in their localization, and in virtually every pro ...
The GABAA receptor is the major molecular target for the action of many drugs in the brain 397
Neurosteroids, which may be physiological endogenous modulators of brain activity, enhance GABAA receptor function 399
The three-dimensional structures of ligand-gated ion channel receptors are being modeled successfully 399
Mouse genetics reveal important functions for GABAA receptor subtypes 400
GABA is the Major Rapidly Acting Inhibitory Neurotransmitter in Brain 400
References 400
19. Purinergic Signaling 402
Nomenclature of Purines and Pyrimidines 402
Purine Release 402
Extracellular nucleotides are regulated by ectoenzymes 404
There are several sources of extracellular adenosine 404
Purinergic Receptors 407
There are four adenosine receptor subtypes 407
Adenosine A1 receptors (A1R) 408
A2A adenosine receptors are highly expressed in the basal ganglia 408
A2B adenosine receptors regulate vascular permeability 409
A3 adenosine receptors are few in number in the central nervous system 409
P2 receptors are subdivided into ionotropic P2X receptors and metabotropic P2Y receptors 409
Effects of Purines in the Nervous System 409
ATP-adenosine is an important glial signal 409
Myelination and importance of the axonal release of ATP 410
Astrocyte-mediated, adenosine-dependent heterosynaptic depression 410
Behavioral roles for glial-derived ATP and adenosine: respiration and sleep 410
pH-dependent release of purines from astrocytes controls breathing 411
Microglia and their response to injury 411
Adenosine and the effects of alcohol 412
Disorders of the Nervous System—Purines and Pain: A1R, P2X and P2Y Receptors 412
Disorders of the Nervous System: Adenosine Kinase and the Adenosine Hypothesis of Epilepsy 412
Disorders of the Nervous System: Parkinson’s Disease and A2A Antagonists 412
Concluding Comments 413
References 413
20. Peptides 415
Neuropeptides 415
Many neuropeptides were originally identified as pituitary or gastrointestinal hormones 415
Peptides can be grouped by structural and functional similarity 416
The function of peptides as first messengers is evolutionarily very old 417
Various techniques are used to identify additional neuropeptides 417
The neuropeptides exhibit a few key differences from the classical neurotransmitters 417
Neuropeptides are often found in neurons with conventional neurotransmitters 418
The biosynthesis of neuropeptides is fundamentally different from that of conventional neurotransmitters 419
Many of the enzymes involved in peptide biogenesis have been identified 419
Neuropeptides are packaged into large, dense-core vesicles 424
Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modification 424
Neuropeptide Receptors 425
Most neuropeptide receptors are seven-transmembrane-domain, G-protein–coupled receptors 425
Neuropeptide receptors are not confined to synaptic regions 426
Expressions of peptide receptors and the corresponding peptides are not well matched 427
The amiloride-sensitive FMRF-amide-gated sodium ion channel is among the few peptide-gated ion channels identified 427
Neuropeptide receptors are becoming molecular targets for therapeutic drugs 427
Neuropeptide Functions and Regulation 427
The study of peptidergic neurons requires a number of special tools 427
Peptides play a role in the plurichemical coding of neuronal signals 428
Neuropeptides make a unique contribution to signaling 428
Regulation of neuropeptide expression is exerted at several levels 428
Peptidergic Systems in Disease 429
Diabetes insipidus occurs with a loss of vasopressin production in the Brattleboro rat model 429
Mutations and knockouts of peptide-processing enzyme genes cause a myriad of physiological problems 429
Neuropeptides play key roles in appetite regulation and obesity 430
Enkephalin knockout mice reach adulthood and are healthy 430
Neuropeptides are crucial to pain perception 431
References 431
III. INTRACELLULAR SIGNALING 434
21. G Proteins 436
Heterotrimeric G Proteins 436
The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptions 436
Multiple forms of heterotrimeric G protein exist in the nervous system 437
Each G protein is a heterotrimer composed of single a, ß and . subunits 437
The functional activity of G proteins involves their dissociation and reassociation in response to extracellular signals 437
G proteins couple some neurotransmitter receptors directly to ion channels 437
G proteins regulate intracellular concentrations of second messengers 439
G proteins have been implicated in membrane trafficking 440
G protein ß. subunits subserve numerous functions in the cell 440
The functioning of heterotrimeric G proteins is modulated by other proteins 441
G proteins are modified covalently by the addition of long-chain fatty acids 443
The functioning of G proteins may be influenced by phosphorylation 443
Small G Proteins 443
The best-characterized small G protein is the Ras family, a series of related proteins of 21 kDa 443
Rab is a family of small G proteins involved in membrane vesicle trafficking 444
Other Features of G Proteins 444
G proteins can be modified by ADP-ribosylation catalyzed by certain bacterial toxins 444
G proteins are implicated in the pathophysiology and treatment of disease 445
References 446
22. Cyclic Nucleotides in the Nervous System 448
Introduction: Second Messengers 448
Adenylyl Cylcases 448
Biochemistry of cAMP production 448
Adenylyl cyclase isozymes: expression and regulation 450
Group 1 adenylyl cyclases 450
Adenylyl Cyclase 1 450
Adenylyl Cyclases 3 and 8 451
Group 2 adenylyl cyclases 451
Adenylyl Cyclase 2 451
Adenylyl Cyclase 4 and 7 451
Group 3 adenylyl cyclases 452
Adenylyl Cyclase 5 452
Adenylyl Cyclase 6 452
Group 4 adenylyl cyclase 452
Soluble adenylyl cyclase 452
Models for cellular regulation of the different types of adenylyl cyclase 452
Long-term regulation of adenylyl cyclases 454
Molecular targets of cAMP 454
Protein kinase A 454
Cyclic nucleotide-gated channels 454
Epac 455
Functions of cAMP signaling in the brain 455
Synaptic plasticity, learning, and memory 455
Pain 455
Dopamine signaling in the striatum 455
Neurodegeneration 455
Drugs of abuse 455
Olfaction 455
Guanylyl Cyclases 455
Membrane-bound guanylyl cyclase 456
GC-A, -B and -C are receptors for natriuretic peptides 457
GC-D and GC-G are implicated in olfaction 457
GC-E and GC-F are involved in photoreceptor signal transduction 457
Soluble guanylyl cyclases 457
sGC is regulated by nitric oxide (NO) 458
Molecular effectors of cGMP signaling 458
Protein kinase G 458
cGMP-gated ion channels 458
Phosphodiesterases 458
Functions of cGMP signaling in the brain 458
Synaptic plasticity, learning, and memory 459
Cognition and mood 459
Pain 459
Phosphodiesterases 459
Structure of phosphodiesterases 459
Families of phosphodiesterases 459
Ca2+/calmodulin-stimulated PDEs (PDE1) 459
cGMP-regulated PDEs (PDE2, PDE3, and PDE11) 460
G protein–activated phosphodiesterase in retinal phototransduction: PDE6 461
PDEs regulated primarily by phosphorylation: PDE4, 5 and 10 462
PDE7, 8 and 9 463
Phosphodiesterases as pharmacological targets 463
Spatiotemporal Integration and Regulation of Cyclic Nucleotide Signaling in Neurons 463
Conclusion and Future Perspective 464
References 464
23. Phosphoinositides 467
Introduction 467
The Inositol Lipids 468
The three quantitatively major phosphoinositides are structurally and metabolically related 468
The quantitatively minor 3'-phosphoinositides are synthesized by phosphatidylinositol 3-kinase 469
Phosphoinositides are dephosphorylated by phosphatases 470
Phosphoinositides are cleaved by a family of phosphoinositide-specific phospholipase C (PLC) isozymes 471
The Inositol Phosphates 473
D-myo-inositol 1,4,5-trisphosphate [i(1,4,5)p3] is a second messenger that liberates Ca2+ from the endoplasmic reticulum via… 473
The metabolism of inositol phosphates leads to regeneration of free inositol 474
Highly phosphorylated forms of myo-inositol are present in cells 474
Diacylglycerol 474
Protein kinase C is activated by the second messenger diacylglycerol 474
Phosphoinositides and Cell Regulation 476
Inositol lipids can serve as mediators of other cell functions, independent of their role as precursors of second messengers 476
Membrane trafficking 476
Cell growth and cell survival 477
Regulation of ion channel activity 477
References 478
24. Calcium 480
The Calcium Signal in Context 480
Calcium Measurement 481
Much of our understanding of the essential role of Ca2+ in cellular physiology has been indirect 481
Current optical methods to measure calcium use chemical or protein-based fluorescent indicators 481
The optical monitoring of [Ca2+] relies on indicators whose fluorescence changes upon binding to calcium 481
Increased resolution can be accomplished optically or by targeting indicator proteins 482
Calcium Homeostasis at the Plasma Membrane 482
The balance between calcium efflux and influx at the plasma membrane determines [Ca2+] 482
Efflux pathways — pumps and transporters 483
Influx pathways — Ca enters the cell through four major routes 483
Cellular Organelles and Calcium Pools 483
The endoplasmic reticulum is the primary intracellular calcium store 484
The ER has pumps, storage buffersand Ca2+ release channels 484
Activation of different ER signaling pathways elicit different responses 484
Store-operated Ca2+ entry: The ER signals when empty to open channels in the plasma membrane 485
Mitochondria have a complex impact on Ca2+ dynamics 485
Ca2+ Signaling Begins in Microdomains 486
Local and Global Ca2+ Signaling: Integrative Roles for Astrocytes? 486
Electrically silent astrocytes use Ca2+ as a signaling molecule 486
The tripartite synapse: gliotransmitters and modulation of transmission at the synapse 487
Astrocyte control of cerebral vasculature 488
Conclusions 489
References 490
25. Serine and Threonine Phosphorylation 492
Protein Phosphorylation is a Fundamental Mechanism Regulating Cellular Functions 492
Phosphorylation levels of substrate proteins are regulated by antagonistic actions of protein kinases and protein phosphatases 493
Protein Ser/Thr Kinases 495
Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation 495
Second messenger–dependent protein Ser/Thr kinases 498
cAMP-dependent protein kinase 498
cGMP-dependent protein kinase 498
Protein kinase C 498
Calcium2+/calmodulin-dependent kinases 500
Second messenger–independent protein Ser/Thr kinases 501
The MAPK cascade is a classical example of second messenger–independent protein Ser/Thr kinase signaling 501
Extracellular signal-regulated protein kinases (ERKs) 502
p38 MAPKs 502
c-Jun NH2-terminal kinases 502
The brain contains many other types of second messenger–independent protein Ser/Thr kinases 503
Cyclin-dependent kinase 5 (CDK5) 503
Glycogen-synthase kinase-3 (GSK3) 503
Casein kinase 1 (CK1) 503
Protein phosphatase 1 (PP1) 504
Protein phosphatase 2A (PP2A) 505
Protein phosphatase 2B (PP2B) 505
Protein phosphatase 2C (PP2C) 506
Dual-specificity phosphatases (DUSPs) 506
Protein Ser/Thr Phosphatases 504
Common strategies used for the evaluation of neuronal functions of protein kinases and phosphatases 506
Neuronal Phosphoproteins 507
Phosphorylation can influence protein function in various ways 507
Proteins are often subject to complex phosphoregulation 508
Cellular signals converge at the level of protein phosphorylation pathways 508
Protein Phosphorylation is a Fundamental Mechanism Underlying Synaptic Plasticity and Memory Functions 509
Presynaptic mechanisms regulated by protein phosphorylation 510
Postsynaptic mechanisms regulated by protein phosphorylation 512
Extrasynaptic mechanisms regulated by protein phosphorylation 514
Protein Phosphorylation in Human Neuronal Disorders 514
Genetic neuronal disorders due to mutations in genes of protein kinases and phosphatases 514
Protein phosphorylation in pathophysiological processes in diseases of the nervous system 515
Protein phosphorylation and AD 515
Acknowledgments 516
References 516
26. Tyrosine Phosphorylation 518
Tyrosine Phosphorylation in the Nervous System 518
Protein Tyrosine Kinases 519
Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper… 519
Receptor protein tyrosine kinases consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domain 523
RPTK Activation 525
RPTK Inactivation 525
Tyrosine Phosphorylation of RPTKs 526
Protein Tyrosine Phosphatases 526
Protein tyrosine phosphatases are structurally different from serine–threonine phosphatases and contain a cysteine residue… 528
Nonreceptor tyrosine phosphatases are cytoplasmic and have regulatory sequences flanking the catalytic domain 529
Receptor protein tyrosine phosphatases consist of an extracellular domain, a transmembrane domain and one or two intracellular… 530
Dual-specificity phosphatases are a diverse family defined by the signature cysteine-containing motif of PTPs 530
Role of Tyrosine Phosphorylation in the Nervous System 530
Tyrosine phosphorylation is involved in every stage of neuronal development 530
Tyrosine phosphorylation has a role in the formation of the neuromuscular synapse 534
Tyrosine phosphorylation contributes to the formation of synapses in the central nervous system 534
Acetylcholine Receptors 535
N-Methyl-d-Aspartate Receptors 535
GABA Receptors 536
Voltage-Gated Ion Channels 536
References 536
27. Transcription Factors in the Central Nervous System 539
The Transcriptional Process 539
Co-regulators of transcription—modulation of chromatin structure 541
Histone acetylation 541
Histone and DNA methylation 542
Regulation of Transcription by Transcription Factors 543
Technology that has hastened the study of transcription 543
NextGen sequencing to assess the cellular transcriptome 545
Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors 546
Corticosteroid receptors regulate transcription in the nervous system 547
The mechanisms of corticosteroid receptor regulation of transcription have been elucidated 547
camp Regulation of Transcription 549
The cAMP response element–binding protein is a member of a family containing interacting proteins 550
The function of the cAMP response element–binding protein has been modeled in transgenic organisms 550
The Role of Transcription Factors in Cellular Phenotype 552
Transcription factors navigate the roadmap of cellular maturation 552
Ectopic expression of transcription factors can reprogram differentiated cells to induce “stemness” 552
The Transcriptome Dictates Cellular Phenotype 553
Transcription as a Target for Drug Development 553
References 554
IV. GROWTH, DEVELOPMENT AND DIFFERENTIATION 556
28. Development of the Nervous System 558
Introduction 558
Early Embryology of the Nervous System 559
The CNS arises from the neural tube 559
The major divisions of the CNS are identifiable early in development 559
Spatial Regionalization 559
A dorsoventral pattern arises with signals from adjacent non-neuronal cells 559
The rostrocaudal axis is specified by homeobox-containing genes 560
Embryonic signaling centers organize large regions of the brain 563
Neurogenesis and Gliogenesis 564
Neurons have a birthdate 564
Reelin and notch signaling contribute to cortical layer organization 564
Neuronal specification involves proneural and neurogenic gene gunctions 565
PNS Development and Target Interactions 566
The neural crest gives rise to PNS derivatives by induction 566
Axon Guidance Contributes to Correct Connections 567
Naturally occurring cell death eliminates cells and synapses 567
Synapse Formation 568
The neuromuscular junction between motor neurons and muscle cells 568
Activity and Experience Shape Long-Lasting Connections 568
Summary 569
References 570
29. Growth Factors 571
Introduction: What is a Growth Factor? 571
Neurotrophins 572
Nerve growth factor 572
Brain-derived neurotrophic factor 573
Neurotrophin 3 575
Neurotrophin 4 575
Regulation of Neurotrophin Expression 576
Proneurotrophins 576
Neurotrophin Receptors 576
Trk receptors 577
The p75 neurotrophin receptor (p75NTR) 577
Glial Cell line–Derived Neurotrophic Factor (GDNF) 578
GFL Receptors 579
Neuregulins 580
Neurotrophic Cytokines 580
Summary and Conclusions 582
References 582
30. Stem Cells in the Nervous System 583
Introduction/Overview 583
Stem Cells are Multipotent and Self-Renewing 583
Embryonic stem (ES) cells are derived from the inner cell mass of embryos 584
Hematopoietic stem cells (HSC) in bone marrow reconstitute the blood 584
Neural Stem Cells Contribute to Neurons and Glia During Normal Development 584
Neural stem cells (NSCs) 585
Radial glia are stem cells 585
The peripheral nervous system (PNS) is derived from neural crest stem cells 585
Stem Cells can be Identified Antigenically and Functionally 586
Stem cell markers in the nervous system 586
The neurosphere functional assay 586
Is there a brain neoplasm stem cell? 587
Induced pluripotent stem cells, reprogramming and directed differentiation 587
Stem Cells Offer Potential for Repair in the Adult Nervous System 588
Stem cells to replace depleted neurochemicals: Parkinson’s disease 588
Stem cell treatment to deliver missing enzymes or proteins: leukodystrophies 589
Stem cells for cell replacement therapy: myelin 589
Stem cells as a source of growth factors and guidance cues 590
Stem cells for immunomodulation: multiple sclerosis 591
Common challenges for stem cell therapy in the nervous system 591
References 592
31. Formation and Maintenance of Myelin 594
Introduction 594
Myelination occurs during nervous system development and is essential for normal nervous system function 595
Schwann Cell Development 595
Schwann cells are the myelinating cells of the peripheral nervous system 595
Schwann cell lineage differentiation is regulated by a series of transcription factors 595
Oligodendrocyte Development 595
Oligodendrocytes are the myelinating cells of the CNS 595
Much early work was possible because of in vitro analysis of the oligodendrocyte cell lineage 595
The discovery of several transcription factors that are expressed at early stages of oligodendrocyte specification and… 596
A number of transcriptional and epigenetic regulators control oligodendrocyte progenitor cell differentiation into… 597
Regulation of Myelination 599
Extensive recent research has focused on identifying the axonal signals that regulate myelination 599
Developmental and Metabolic Aspects of Myelin 600
Synthesis of myelin components is very rapid during deposition of myelin 600
Sorting and transport of lipids and proteins takes place during myelin assembly 600
The composition of myelin changes during development 601
Genetic Disorders of Myelination 601
Rodent mutants of myelination have been investigated since the 1950s 601
Myelin Maintenance 602
Maintenance of myelin once it is formed is a poorly understood process 602
Myelin components exhibit great heterogeneity of metabolic turnover 602
There are signal transduction systems in myelin sheaths 602
The dynamic nature of myelin sheaths likely contributes to the functional state of axons 603
Peripheral neuropathies result from loss of myelin in the peripheral nervous system 603
A number of environmental toxins impact myelination during development or myelin maintenance in the adult 603
Leukodystrophies define a number of genetic disorders that impact CNS myelination (dysmyelination) or myelin maintenance once… 603
Remyelination 604
Peripheral nerve regeneration has been studied extensively 604
Demyelination in the CNS has far more extensive long-term consequences than in the PNS, since a single oligodendrocyte can… 605
Acknowledgments 605
References 605
32. Axonal Growth in the Adult Mammalian Nervous System: Regeneration and Compensatory Plasticity 607
Introduction 607
Regeneration in the Peripheral Nervous System 608
Wallerian degeneration is the secondary disruption of the myelin sheath and axon distal to the injury 608
The molecular and cellular events during Wallerian degeneration in the PNS transform the damaged nerve into an environment… 608
Both Schwann cells and basal lamina are required for axonal regeneration to proceed 609
Cell surface adhesion molecules, which promote regeneration, are expressed on plasmalemma of both Schwann cells and regenerating… 610
Structural and biochemical changes occur after axotomy 610
Regeneration in the Central Nervous System 610
Central nervous system myelin contains molecules that inhibit neurite growth 610
Nogo-A is a potent inhibitor of neurite growth and blocks axonal regeneration in the central nervous system 611
Nogo gene is a member of the reticulon superfamily 612
Nogo-A function-blocking antibodies and peptides lead to axonal growth and functional recovery in vivo 613
Lines of knockout mice null for the Nogo genes have been developed 613
Additional myelin components have growth-inhibitory activity 613
Inhibition of neurite growth is mediated through surface receptors and intracellular signaling molecules 614
Neuronal expression of Nogo-A regulates neurite outgrowth 614
Axon growth is inhibited by the glial scar 614
Neurotrophic factors promote both cell survival and axon growth after adult CNS injury in vivo 615
Central Nervous System Injury and Compensatory Plasticity 615
Neonatal brain damage results in compensatory plasticity 615
Compensatory plasticity and functional recovery can be enhanced in the injured adult central nervous system through blockade… 616
Summary 617
Acknowledgments 618
References 618
V. CELL INJURY AND INFLAMMATION 620
33. Molecular Mechanisms and Consequences of Immune and Nervous System Interactions 622
Introduction 622
Definition: What is neuroimmunology? 622
Scope: Are neuroimmune interactions relevant only in the context of immune-mediated neurodegenerative disorders? 623
Relevance: A real-world example 623
Distinguishing Friend from FOE 624
Innate versus adaptive immunity: two interacting types of immune recognition 624
Innate immunity is triggered by evolutionarily conserved alarm signals 624
Adaptive immunity can recognize evolutionarily novel molecules 624
Antigen presentation by major histocompatibility-complex–expressing cells is required to activate T-cells 624
Antigen-activated T-cells regulate the activation of innate immune cells 626
The activation state of the antigen-presenting cell regulates T cell activation and phenotype 626
Choosing between immune tolerance and inflammation 626
Antigen presentation in the absence of alarm signals promotes tolerance 627
PAMP and DAMP signals shape APC function and T-cell differentiation 627
The Nervous System Regulates Both Innate and Adaptive Immunity 627
Functional consequences of lymphoid tissue innervation 627
Neuropeptides are potent modulators of antigen-presenting cell function 628
Immune Privilege Is Not Immune Isolation: The CNS as an Immune-Active Organ 628
The BBB and CNS-specific regulation of leukocyte influx and efflux 629
Leukocyte migration into the CNS parenchyma is a two-step process 629
Microglia, a CNS-specific macrophage and antigen-presenting cell 630
Distinguishing CNS-resident microglia from CNS-infiltrating macrophages 630
Microglia are not effective at initiating antigen-driven T-cell functions 631
The CNS microenvironment actively regulates the phenotype of microglia and infiltrating immune cells 631
Immune-Regulated Changes in Neuronal Function and Mammalian Behavior 632
Summary: Manipulating Neuroimmune Interactions 633
References 633
34. Neuroinflammation 635
Neuroinflammation: Introduction 635
The role of microglia in neuroinflammation 636
The Highly Regulated Activation of Microglia and Phagocytosis 637
Microglial activation 637
Microglial phagocytosis 637
Receptors in microglia 637
Microglia in neurodegenerative diseases 638
Microglial Dysfunction During Aging 638
Protein Aggregation 638
The effects of protein aggregation on microglial function 639
Cytokines/Chemokines 639
Cytokines are responsible for microglia activation 639
Cytokines are produced by activated microglia 639
Anti-inflammatory interleukin-10 and TGF-ß1 639
Lipid Mediator Pathways in Neuroinflammation 639
Initiation of inflammation: prostaglandin and leukotriene pathways 639
Resolution of inflammation: lipoxin, resolvin, and neuroprotectin pathways 641
Ischemia-Reperfusion Damage 641
The Interface Between Inflammation and the Immune System in the CNS 641
Aß Immunotherapy 641
The inflammasome 641
Mitochondria: A Connection Between Inflammation and Neurodegeneration 642
Neuroprotective Signaling Circuits 642
References 643
35. Brain Ischemia and Reperfusion: Cellular and Molecular Mechanisms in Stroke Injury 646
Brain Responses to Ischemia 646
Focal cerebral ischemia 647
Global cerebral ischemia 648
Injury in the Ischemic Phase 652
Excitotoxic glutamate neurotransmitter 652
Excitotoxicity 652
Ca2+ overloading in the ischemic injury 652
NMDA receptors, brain function and cell death 653
Downstream cell death signals of NMDA receptors 654
Brain Injury During the Reperfusion Phase: Free Radicals in Ischemia–Reperfusion Injury 654
Reactive oxygen species contribute to the injury 654
Mitochondria, nitric oxide synthase and polyunsaturated fatty acid metabolism are sources of reactive oxygen species during… 655
Polyunsaturated fatty acids generate reactive oxygen species 655
Brain antioxidants contribute to the protection of brain from ischemia–reperfusion injury 655
Reactive oxygen species enhance the excitotoxic and the apoptotic consequences of ischemic brain damage 656
Breakdown of the Neurovascular Unit and Brain Edema 656
Metalloproteinases during the neurovascular unit disruption 656
Significance of aquaporins in brain edema 657
Neuroprotection Signaling and Resolution of Inflammation: Mechanisms 657
Inflammatory mediators and anti-inflammatory regulation 657
Apoptotic signaling 658
Docosanoids and penumbra protection 660
Potential Therapeutic Strategies for Acute Ischemic Stroke 663
Acknowledgments 665
References 665
36. Lipid Mediators: Eicosanoids, Docosanoids and Platelet-Activating Factor 668
Storage of Lipid Messengers in Neural Membrane Phospholipids 669
Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli 669
Specific lipid messengers are cleaved from reservoir phospholipids by phospholipases upon activation by various stimuli 670
Phospholipids in synaptic membranes are an important target in seizures, traumatic brain injury, neurodegenerative diseases… 670
Some molecular species of phospholipids in excitable membranes are reservoirs of bioactive lipid mediators that act as… 670
Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second… 670
Phospholipases A2 672
Phospholipases A2 catalyze the cleavage of the fatty acyl chain from the sn-2 carbon of the glycerol backbone of phospholipids 672
Cytosolic phospholipases A2 are involved in bioactive lipid formation 672
Ischemia and seizures activate phospholipases A2, releasing arachidonic and docosahexaenoic acids 672
Secretory phospholipases A2 are of relatively low molecular weight and have a high number of disulfide bridges, making them… 672
There are high-affinity receptors that bind secretory phospholipases A2 672
Eicosanoids 673
Arachidonic acid is converted to biologically active derivatives by cyclooxygenases and lipoxygenases 673
Prostaglandins are very rapidly released from neurons and glial cells 673
Arachidonic acid is also the substrate for lipoxygenases and, as in the case of cyclooxygenases, molecular oxygen is required 674
Platelet-Activating Factor 674
Platelet-activating factor is a very potent and short-lived lipid messenger 675
Ischemia and seizures increase platelet-activating factor content in the brain 677
Cyclooxygenases 677
The cyclooxygenases are heme-containing enzymes that convert arachidonic acid to prostaglandin H2 677
Platelet-activating factor is a transcriptional activator of cyclooxygenase-2 677
COX-derived AA metabolites play multiple important roles in CNS 677
Cyclooxygenase-2 participates in aberrant synaptic plasticity during epileptogenesis 677
Lipoxygenases 678
The lipoxygenases are involved in the rate-determining step in the biosynthesis of leukotrienes, lipoxins, resolvins, and protectins 678
5-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 5-position to form 5-HpETE 678
15-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 15-position to Form 15-HpETE 678
LOs and LO-derived products play important roles in a variety of inflammatory disorders 679
Diacylglycerol Kinases 679
The slow glutamate responses are mediated through metabotropic receptors coupled to G proteins 679
Lipid Signaling in Neuroinflammation 679
A platelet-activating-factor-stimulated signal-transduction pathway is a major component of the kainic-acid-induced… 679
In cerebrovascular diseases, the phospholipase-A2-related signaling triggered by ischemia–reperfusion may be part of a delicate… 679
Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, are products of membrane lipid breakdown… 679
Free fatty acid release during cerebral ischemia is a complex process that includes the activation of signaling cascades 680
The rate of free fatty acid production in the mammalian brain correlates with the extent of resistance to ischemia 681
Activation of the arachidonic acid cascade during ischemia–reperfusion is a multistage process 681
Cyclooxygenase and lipoxygenase products accumulate during reperfusion following cerebral ischemia 681
The cerebrovasculature is also an abundant source of eicosanoids 681
Docosahexaenoic Acid 681
Brain and retina are the tissues containing the highest contents of docosahexaenoic acid 681
Rhodopsin in photoreceptors is immersed in a lipid environment highly enriched in phospholipids containing docosahexaenoic… 681
Lipid Peroxidation and Oxidative Stress 682
Docosahexaenoic-acid–containing phospholipids are targets for lipid peroxidation 682
Docosanoids 682
Sequential oxygenation of DHA leads to several types of potent bioactive lipid mediators, including resolvins and protectins 682
Neuroprotectin D1: A Docosahexaenoic-Acid–Derived Mediator 682
Docosanoids, enzyme-derived docosahexaenoic acid metabolites, were identified initially in the retina 682
Neuroprotectin D1 is a potent inhibitor of brain ischemia–reperfusion-induced PMN infiltration, as well as of NF-.B and COX-2 expression 682
The Future of Neurolipidomic Signaling 682
Knowledge of the significance of lipid signaling in the nervous system is being expanded by advances in experimental approaches 682
Understanding of the fundamental workings of the dendrites, which contain complex intracellular membranes rich in polyunsaturated… 683
Arachidonic acid is widely implicated in signaling in brain, and research continues toward understanding the release of this fatty… 683
The knowledge evolving from lipidomic neurobiology will be potentiated by multidisciplinary approaches such as multiphoton… 685
References 685
37. Apoptosis and Necrosis 688
Distinguishing Features of Apoptosis and Necrosis 688
During embryonic and postnatal development, and throughout adult life, many cells in the nervous system die 688
Many of the morphological and biochemical changes that occur in cells that die by necrosis are very different from those that occur in apoptosis 689
Apoptosis 689
Adaptive apoptosis occurs in the developing and adult nervous system 689
Apoptosis occurs in acute neurological insults 690
Apoptosis occurs in neurodegenerative disorders 692
There are many triggers of apoptosis 693
Insufficient trophic support 693
Death receptor activation 693
DNA damage 693
Oxidative and metabolic stress 693
Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process 694
Several different changes in mitochondria occur during apoptosis 695
The postmitochondrial events of apoptosis include activation of the caspases 695
A widely used criterion for identifying a cell as ‘apoptotic’ is nuclear chromatin condensation and fragmentation 695
Cells in the nervous system possess different mechanisms to prevent apoptosis 695
Neurotrophic factors, cytokines and cell adhesion molecules 695
Antiapoptotic proteins 696
Hormesis-based mechanisms 696
Antioxidants and calcium-stabilizing proteins 696
The morphological and biochemical characteristics of apoptosis are not always manifest in cells undergoing programmed cell ... 697
Apoptotic cascades can be triggered, and pre- and postmitochondrial events can occur, without the cell dying 697
Necrosis 697
Necrosis is a dramatic and very rapid form of cell death in which essentially every compartment of the cell disintegrates 697
There are few cell death triggers that are only capable of inducing either apoptosis or necrosis 697
Trauma 697
Energy failure/ischemia 697
Excitotoxicity 698
TARGETING Apoptosis and Necrosis in Neurological DISORDERS 698
References 700
VI. INHERITED AND NEURODEGENERATIVE DISEASES 702
38. Peripheral Neuropathy: Neurochemical and Molecular Mechanisms 704
Introduction 704
Peripheral Nerve Organization 705
The peripheral nervous system (PNS) includes the cranial nerves, the spinal nerves and nerve roots, the peripheral nerves… 705
Genetically Determined Neuropathies 705
The inherited neuropathies are commonly referred to as Charcot-Marie-Tooth disorders (CMT) or hereditary motor and sensory… 705
Diabetic Neuropathy 709
Metabolic/Endocrine diseases such as diabetes mellitus (DM), thyroid diseases, and uremia are frequent causes of peripheral nerve damage 709
Autoimmune Neuropathies 709
An autoimmune attack on the PNS can manifest in various disease forms that include but are not limited to Guillain-Barré… 709
Other Causes of Peripheral Nerve Disorders 712
Infections can damage nerves directly, via exotoxins, or by immune mechanisms 712
Peripheral nerve damage is a recognized complication of toxins (e.g., alchohol, heavy metals, hexacarbons, organophosphates… 712
Nutritional and vitamin deficiencies that occur during famine, after gastric surgery for tumors, or, more recently, following… 712
Axon Degeneration and Protection 712
References 713
39. Diseases Involving Myelin 716
General Classification 717
Myelin deficiency can result from failure of synthesis during development or from myelin breakdown after its formation 717
Many of the biochemical changes associated with CNS demyelination are similar regardless of etiology 717
Acquired Immune-Mediated and/or Infectious Diseases of Myelin 717
Nervous system damage in acquired demyelinating diseases is selectively against myelin or myelin-forming cells, but axons… 717
Multiple sclerosis (MS) is the most common demyelinating disease of the CNS in humans 717
Diagnosis 717
Pathology 718
Gray matter lesions 718
Axonal and neuronal pathology 719
Biochemistry 719
Therapy 720
Etiology 720
Epidemiology and natural history of MS 720
Environmental factors 720
Genetics 721
Immunology 721
Perspectives for future research 721
Animal models are required to understand the pathogenesis of MS and test the efficacy of possible therapeutic interventions 721
Viral models 721
Experimental allergic encephalomyelitis 722
Toxins 722
Other acquired disorders affecting CNS myelin have an immune-mediated or infectious pathogenesis 722
Acute disseminated encephalomyelitis 722
Progressive multifocal leukoencephalopathy 722
Some human peripheral neuropathies involving demyelination are immune mediated 722
Paraproteinemic polyneuropathy 723
Guillain–Barré syndrome 723
Chronic inflammatory demyelinating polyneuropathy 724
Genetically Determined Disorders of Myelin 724
The human leukodystrophies are inherited disorders of CNS white matter 724
Lysosomal storage diseases 724
Other leukodystrophies 726
Deficiencies of peripheral nerve myelin in common inherited human neuropathies are caused by mutations in a variety of genes 726
Other Diseases Primarily Involving Myelin 726
Myelin formation and stability are affected by a variety of other etiologies including developmental insults, nutritional… 726
Disorders Primarily Affecting Neurons with Secondary Involvement of Myelin 727
Many insults to the nervous system initially cause damage to neurons but eventually result in regions of demyelination as… 727
Repair in Demyelinating Diseases 727
The capacity for remyelination depends upon the presence of receptive axons and sufficient myelin-forming cells 727
Spontaneous remyelination of lesions of MS is well documented, but remyelination is usually incomplete 728
Remyelination in the CNS can be promoted by various treatments 728
Acknowledgments 728
References 728
40. The Epilepsies: Phenotypes and Mechanisms 730
Epilepsy is a Common Neurological Disorder 730
Terminology and Classification 730
Disrupting the delicate balance of inhibitory and excitatory synaptic transmission can trigger the disordered, synchronous… 731
Cellular mechanisms underlying hyperexcitability have been analyzed by electrophysiological studies of hippocampal slices… 733
Normally the dentate granule cells of hippocampus limit excessive activation of their targets, the CA3 pyramidal cells 733
Analyses of afferents of dentate granule cells from epileptic animals reveal abnormal inhibitory and excitatory synaptic input 734
Axonal and dendritic sprouting lead to abnormal recurrent excitatory synaptic circuits among the dentate granule cells in epileptic brain 734
Epileptogenesis is the process by which a normal brain becomes epileptic 734
Identifying molecular mechanisms of epileptogenesis will provide new targets for developing small molecules to prevent epilepsy 735
Mechanisms of Antiseizure Drugs 736
Many antiseizure drugs act on voltage-gated sodium channels to limit high-frequency, but not low-frequency, firing of neurons 736
Other antiseizure drugs enhance GABA-mediated synaptic inhibition 736
Other antiseizure drugs regulate a subset of voltage-gated calcium currents 737
Genetics of Epilepsy 738
Many forms of epilepsy have genetic determinants 738
Some spontaneous and some engineered mutations of mice result in epilepsy 740
References 742
41. Genetics of Neurodegenerative Diseases 744
Genetic Aspects of Common Neurodegenerative Diseases 744
Alzheimer’s Disease 746
Early onset familial AD 746
Apolipoprotein E in late-onset AD 746
Genome-wide screening in late-onset AD 747
Parkinson’s Disease 748
Autosomal-dominant forms of PD 748
Autosomal-recessive forms of PD 748
Candidate-gene studies and genome-wide screening in PD 749
Dementia with Lewy Bodies 750
The genetics of DLB shows similarities with both PD and AD 750
Frontotemporal Dementia 751
Genetic determinants of tau-positive FTLD 751
Genetic determinants of tau-negative FTLD 751
Amyotrophic Lateral Sclerosis 752
Familial ALS 752
Neurodegenerative Triplet Repeat Disorders 754
Huntington’s disease (HD) 754
Creutzfeld-JaKob Disease and other Prion Diseases 755
PRNP mutations are causal and influence disease progression 755
Concluding Remarks 756
References 758
42. Disorders of Amino Acid Metabolism 762
Introduction 763
An aminoaciduria usually results from the congenital absence of an enzyme needed for metabolism of an amino acid 763
The major metabolic fate of amino acids is conversion into organic acids absent an enzyme to oxidize an organic acid, an organic aciduria results
Untreated aminoacidurias can cause brain damage in many ways, often through impairing brain energy metabolism 763
An imbalance of amino acids in the blood often alters the rate of transport of these compounds into the brain, thereby affecting levels of neurotransmitters… 765
Treatment of aminoacidurias with a low-protein diet may influence brain chemistry 767
Imbalances of brain amino acids may hinder the synthesis of brain lipids, leading to a diminution in the rate of myelin formation 767
In many aminoacidurias, there may occur deficits in neurotransmitters and receptors, particularly the N-methyl-d-aspartate receptor 767
Brain edema, often associated with increased intracranial pressure, may accompany the acute phase of metabolic decompensation in the aminoacidurias 767
Disorders of Branched-Chain Amino Acids: Maple Syrup Urine Disease 767
Maple syrup urine disease involves a congenital failure to oxidize the three branched-chain amino acids 767
Effective treatment of maple syrup urine disease involves the restriction of dietary branched-chain amino acids 768
Disorders of Phenylalanine Metabolism: Phenylketonuria 768
Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase 768
The outlook for patients who are treated at an early age is favorable 769
Rarely, phenylketonuria results from a defect in the metabolism of biopterin, a cofactor for the phenylalanine hydroxylase pathway 769
Disorders of Glycine Metabolism: Nonketotic Hyperglycinemia 769
Nonketotic hyperglycinemia results from the congenital absence of the glycine cleavage system, which mediates the interconversion of glycine and serine 769
Nonketotic hyperglycinemia causes a severe seizure disorder and profound brain damage 769
Treatment for nonketotic hyperglycinemia is less effective than that available for other aminoacidurias 770
Disorders of Sulfur Amino Acid Metabolism: Homocystinuria 770
The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids 770
Homocystinuria is the result of the congenital absence of cystathionine synthase, a key enzyme of the transsulfuration pathway 772
Homocystinuria can be treated in some cases by the administration of pyridoxine (Vitamin B6), which is a cofactor for the cystathionine synthase reaction 772
Patients with homocystinuria are at risk for cerebrovascular and cardiovascular disease and thromboses 772
Prognosis is more favorable in the pyridoxine-responsive patients 772
Homocystinuria can occur when homocysteine is not remethylated back to form methionine 773
One form of remethylation deficit involves defective metabolism of folic acid, a key cofactor in the conversion of homocysteine to methionine 773
Methionine synthase deficiency (cobalamin-E disease) produces homocystinuria without methylmalonic aciduria 773
Cobalamin-c disease: remethylation of homocysteine to methionine also requires an ‘activated’ form of vitamin B12 773
Hereditary folate malabsorption presents with megaloblastic anemia, seizures and neurological deterioration 774
The Urea Cycle Defects 774
The urea cycle is essential for the detoxification of ammonia 774
Urea cycle defects cause a variety of clinical syndromes, including a metabolic crisis in the newborn infant 775
Carbamyl phosphate synthetase deficiency 775
N-Acetylglutamate synthetase deficiency 775
Ornithine transcarbamylase deficiency 775
Citrullinemia 775
Argininosuccinic aciduria 776
Arginase deficiency 776
Urea cycle defects sometimes result from the congenital absence of a transporter for an enzyme or amino acid involved in the urea cycle 776
Hyperornithinemia, hyperammonemia, homocitrullinuria 776
Lysinuric protein intolerance 776
Successful management of urea cycle defects involves a low-protein diet to minimize ammonia production as well as medication… 776
Disorders of Glutathione Metabolism 777
The tripeptide glutathione is the major intracellular antioxidant 777
5-Oxoprolinuria: glutathione synthetase deficiency 777
.-Glutamylcysteine synthetase deficiency 777
.-Glutamyltranspeptidase deficiency 777
5-Oxoprolinase deficiency 777
Disorders of g-Aminobutyric Acid Metabolism 777
Congenital defects in the metabolism of .-aminobutyric acid have been described 777
Pyridoxine dependency 778
.-Aminobutyric acid transaminase deficiency 778
Succinic semialdehyde dehydrogenase deficiency 778
Disorders of N-Acetyl Aspartate Metabolism 778
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
References 778
43. Inborn Metabolic Defects of Lysosomes, Peroxisomes, Carbohydrates, Fatty Acids and Mitochondria 780
Lysosomal Storage Diseases 780
The cell contains specialized organelles for the recycling of waste material: the lysosomes 780
Deficiency of a lysosomal enzyme causes the blockage of the corresponding metabolic pathway, leading to the accumulation of its undigested substrate 781
For most lysosomal storage diseases, definitive cures are not available 782
Lysosomal storage disorders are pleiotropic, depending on the mutation, the enzyme affected and the sites of accumulated products 782
Farber disease 782
Gaucher disease 782
Krabbe disease (globoid cell leukodystrophy) 783
Metachromatic leukodystrophy (MLD) 783
Fabry disease 784
GM2 gangliosidoses (Tay–Sachs disease Sandhoff disease and GM2 activator deficiency)
Niemann–Pick disease, types A and B 785
Niemann–Pick disease type C (NPC) 785
The mucopolysaccharidoses (MPS) 785
Neuronal ceroid lipofuscinoses (NCLs) 785
Peroxisomal Diseases 785
Peroxisomes are specialized organelles for metabolism of oxygen peroxide and of various lipids 785
Peroxisomal dysfunction and the nervous system: peroxisomal defects impair the function of systemic organs and of the nervous system 786
Classification of Peroxisomal Diseases 786
Human diseases involving peroxisomal dysfunction were originally described as syndromes 786
Defects of peroxisomal biogenesis 786
Defects of single peroxisomal enzymes 786
Therapy of Peroxisomal Diseases 787
Diseases of Carbohydrate and Fatty Acid Metabolism 787
Diseases of carbohydrate and fatty acid metabolism in muscle 788
One class of glycogen or lipid metabolic disorders in muscle is manifest as acute, recurrent, reversible dysfunction 788
Phosphorylase deficiency (McArdle disease, glycogenosis type V) exemplifies the glycogenoses causing recurrent muscle “energy crises,” with cramps, myalgia… 788
Genetic defects of phosphorylase b kinase (PHK) 788
Other glycolytic defects involving PFK, PGK, PGAM, and LDH have clinical and pathological features similar to McArdle disease 789
CPT II deficiency has clinical features similar to McArdle disease 791
Other beta-oxidation defects have clinical features similar to McArdle disease 791
A second class of disorders of glucose and fatty acid metabolism causes progressive weakness 791
Acid maltase deficiency (AMD) (glycogenosis type II) 791
Debrancher enzyme deficiency (glycogenosis type III, Cori’s disease, Forbe disease) 792
Branching enzyme deficiency (glycogenosis type IV Andersen’s disease)
Carnitine deficiency 792
Defects in adipose triglyceride lipase (ATGL) 793
The impairment of energy production, be it from carbohydrate or lipids, is expected to lead to common consequences and result in similar exercise-related signs and symptoms 793
Diseases of carbohydrate and fatty acid metabolism in brain 795
Defective transport of glucose across the blood–brain barrier is caused by deficiency in the glucose transporter protein 795
One class of carbohydrate and fatty acid metabolism disorders is caused by defects in enzymes that function in the brain 795
Debrancher enzyme deficiency 795
Branching enzyme deficiency 795
Phosphoglycerate kinase deficiency 796
Lafora disease 796
Another class of carbohydrate and fatty acid metabolism disorders is caused by systemic metabolic defects that affect the brain. Glucose-6-phosphatase deficiency (glycogenosis type I, Von Gierke disease) 796
Fructose-1,6-bisphosphatase deficiency 796
Phosphoenolpyruvate carboxykinase (PEPCK) deficiency 796
Pyruvate carboxylase deficiency 796
Biotin-dependent syndromes 797
Glycogen synthetase deficiency 797
Fatty acid oxidation defects 797
Diseases of Mitochondrial Metabolism 797
Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system 797
Mitochondrial DNA is inherited maternally 798
The genetic classification of mitochondrial diseases divides them into three groups 799
Defects of nuclear DNA 799
Defects of communication between nDNA and mtDNA can also cause mitochondrial diseases 800
Defects in genes controlling mtDNA translation 800
The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism 800
Defects of mitochondrial transport 800
Defects of substrate utilization 800
Defects of the Krebs cycle 801
Defects of oxidation—phosphorylation Coupling 801
Abnormalities of the respiratory chain 801
Abnormalities of the respiratory chain: defects of complex I 801
Abnormalities of the respiratory chain: defects of complex II 802
Abnormalities of the respiratory chain: coenzyme Q10 (CoQ10) deficiency 802
Abnormalities of the respiratory chain: defects of complex III 802
Abnormalities of the respiratory chain: defects of complex IV 802
Abnormalities of the respiratory chain: defects of complex V 803
Acknowledgments and Dedication 804
References 804
44. Disorders of Muscle Excitability 808
Organization of the Neuromuscular Junction 808
Nerve and muscle communicate through neuromuscular junctions 808
Acetylcholine acts as a chemical relay between the electrical potentials of nerve and muscle 810
The fidelity of signal transmission relies on the orchestration of innumerable stochastic molecular events 810
Excitation and Contraction of the Muscle Fiber 811
The excitable apparatus of muscle is composed of membranous compartments 811
Myofibrils are designed and positioned to produce movement and force 811
Calcium couples muscle membrane excitation to filament contraction 812
Genetic Disorders of the Neuromuscular Junction 814
Congenital myasthenic syndromes impair the operation of the acetylcholine receptor 814
ChAT Deficiency 814
AChR Deficiency 814
Rapsyn deficiency 815
Slow channel syndrome 815
Fast channel syndrome 815
Acetylcholinesterase deficiency 815
Hereditary Diseases of Muscle Membranes 815
Mutations of the sodium channel cause hyperkalemic periodic paralysis and paramyotonia congenital 815
Hypokalemic periodic paralysis is due to calcium channel mutations 816
Abnormal potassium channels in Andersen syndrome cause more than periodic paralysis 816
Ribonuclear inclusions are responsible for the multiple manifestations of myotonic dystrophy 816
Congenital myotonia is caused by mutant Cl- channels 817
Malignant hyperthermia caused by mutant ryanodine receptor calcium release channels 817
Calcium channel mutations may also cause malignant hyperthermia 818
Brody disease is an unusual disorder of the sarcoplasmic reticulum calcium ATPase 818
Immune Diseases of Muscle Excitability 818
Myasthenia gravis is caused by antibodies that promote premature AChR degradation 818
Antibodies against MuSK mimic myasthenia gravis 818
Antibodies cause calcium channel dysfunction in Lambert-Eaton syndrome 819
Potassium channel antibodies in Isaac syndrome cause neuromyotonia 819
Toxins and Metabolites that Alter Muscular Excitation 820
Bacterial botulinum toxin blocks presynaptic ACh release 820
Snake, scorpion, spider, fish and snail peptide venoms act on multiple molecular targets at the neuromuscular junction 821
Electrolyte imbalances alter the voltage sensitivity of muscle ion channels 823
References 824
45. Motor Neuron Diseases 826
Amyotrophic Lateral Sclerosis Is the Most Common Adult-Onset Motor Neuron Disease 826
The disease is characterized clinically by weakness, muscle atrophy and spasticity affecting both upper and lower motor neurons 827
Although most cases ALS are sporadic, mutations in several genes may cause familial ALS 828
ALS1 is caused by mutant SOD1 828
ALS2 is linked to mutant Alsin 828
ALS4 is linked to mutations in a helicase gene 828
Angiogenic factors may be linked to ALS 828
Mutant dynactin p150Glued causes fALS 829
VAPB associated with ALS is a ligand for eph receptors 829
ALS is linked to two genes involved in RNA metabolism: TDP-43 and FUS 829
Mutations in OPTN were identified in several japanese patients with ALS 830
Identification of valosin-containing protein (VCP) is linked to fALS by exome sequencing 831
Models of Motor Neuron Disease Induced by Experimental Nerve Injury Have been Instructive 831
Interrupting the communication between the motor neuron cell body and axon by transection, crush or avulsion induces motor neuron injury 831
IDPN induces neurofilamentous axonal pathology 831
Selected Genetic Models of Relevance to ALS and Other Motor Neuron Diseases Have been Identified or Generated 831
Hereditary canine spinal muscular atrophy (HCSMA) is a naturally occurring mutation that produces motor neuron disease 831
Some transgenic mice expressing wild-type or mutant NF genes develop motor neuron disease and neurofibrillary pathology 832
fALS-linked mutant SOD1 mice reproduce many of the clinical and pathological features of ALS 832
Lines of mice harboring other mutant genes may also develop an ALS-like phenotype 832
Mutant dynactin p150glued transgenic mice have MND-like pathology 833
Mutant tubulin-specific chaperone E transgenic mice exhibit progressive motor neuropathy 833
To test the role of NF in mutant SOD1 mice, the latter animals were crossbred to several lines of mice that have altered distributions of NF 833
Vascular endothelial growth factor (VEGF) influences the growth and permeability of blood vessels 833
The molecular mechanisms whereby mutant SOD1 causes selective motor neuron death have yet to be defined 833
Is the toxicity of mutated SOD1 cell-autonomous? 833
Expression of GLT1 is implicated as a possible cofactor 833
Mutation-induced conformational effects and copper oxidative toxicity have been implicated 834
Accumulating evidence supports the view that fALS-associated mutants facilitate misfolding of wild-type SOD1 834
A variety of experimental therapeutic strategies have been tested in mutant SOD1 transgenic mice 834
Available Genetic Mouse Models Will Aid in Discovering Disease Mechanisms and Novel Means of Therapy 834
Acknowledgments 836
References 836
46. Neurobiology of Alzheimer’s Disease 840
Alzheimer’s Disease is the Most Prevalent Neurodegenerative Disease of the Elderly 840
The clinical syndrome, ranging from mild cognitive impairments to severe dementia, reflects biochemical and cellular abnormalities in specific regions and circuits in the brain 841
Advances in laboratory measurements and imaging are of value in establishing the diagnosis of AD 841
Familial forms of AD are associated with mutations in select genes inherited as autosomal dominants, while variants in other genes can lead to increased risk of sporadic AD 842
APP Mutations are Linked to fAD 842
Mutations in PS1 and PS2 are Linked to fAD 842
Multiple neurotransmitter circuits and brain networks are damaged in AD 842
Neuritic plaques, one of the pathological hallmarks of AD, are composed of swollen neurites, extracellular deposits of Aß 40-42 peptides derived from… 843
Neurofibrillary tangles (NFT), another characteristic feature of AD, are composed of intracellular bundles of paired helical filaments (PHF), which represent… 843
Aspartyl proteases carry out the ß- and g-secretase cleavages of APP to generate Aß peptides 844
Transgenic strategies have been used to create models of Aß amyloidosis and tauopathies 845
Gene targeting approaches have identified and validated targets for therapy 846
Transgenic mouse models are being used to test a variety of novel therapies 847
Conclusions 848
Acknowledgments 850
References 850
47. Synucleinopathies and Tauopathies 854
Introduction 854
Synucleins 855
The human synuclein family consists of three members 855
Synucleins are lipid-binding proteins 855
Parkinson’s Disease and Other Lewy Body Diseases 856
SNCA mutations cause familial Parkinson’s disease 856
Lewy body filaments are made of a-synuclein 856
The development of a-synuclein pathology is not random 857
Other genes are implicated in Parkinson’s disease 857
Multiple System Atrophy 858
Synthetic a-Synuclein Filaments 858
Animal Models of Synucleinopathies 858
Rodents and primates 858
Flies, worms and yeasts 859
Synucleinopathies—Outlook 859
Microtubule-Associated Protein Tau 859
Six tau isoforms are expressed in adult human brain 859
Tau is a phosphoprotein 860
Tau and Alzheimer’s Disease 860
The paired helical filament is made of tau protein 860
Filamentous tau is hyperphosphorylated 860
The development of tau pathology is not random 861
Other Tauopathies 861
Other taupathies include progressive supranuclear palsy, corticobasal degeneration and Pick’s disease 861
MAPT Mutations Causing Tauopathy 861
FTD is characterized by atrophy of the frontal and temporal lobes of the cerebral cortex, with additional subcortical changes 861
MAPT mutations are exonic or intronic 861
Relevance for Other Tauopathies 862
Synthetic Tau Filaments 863
Animal Models of Human Tauopathies 863
Rodents and fish 863
Flies, worms and yeasts 865
Tauopathies—Outlook 866
References 866
48. Cellular and Molecular Basis of Neurodegeneration in the CAG–Polyglutamine Repeat Diseases 869
Introduction to the CAG–Polyglutamine Repeat Diseases 869
CAG repeat expansions are responsible for nine inherited neurodegenerative disorders 869
Normal functions of polyglutamine disease proteins 870
Expanded Polyglutamine Tracts Promote Protein Misfolding to Drive Neurotoxicity 870
Disease-length polyglutamine tracts adopt a novel, toxic conformation 870
Polyglutamine disease proteins form aggregates visible at the light microscope level 870
Polyglutamine disease proteins exist as misfolded monomers, oligomers and protofibrils 871
What is the toxic misfolded protein species in the polyglutamine repeat diseases? 871
The Role of Protein turnover Pathways in Polyglutamine Disease Pathogenesis 871
Are polyglutamine tracts substrates for the ubiquitin-proteasome system and autophagy pathways? 871
Autophagy pathway involvement in polyglutamine neurodegeneration 872
Evidence for autophagy dysfunction in the polyglutamine repeat diseases 874
The Importance of Normal Function in the Polyglutamine Repeat Diseases 874
Interference with ataxin-7’s function as a transcription regulatory protein in SCA7 874
Ataxin-1 protein complex associations account for SCA1 disease pathogenesis 874
Post-translational modifications as determinants of disease 874
Phosphorylation 874
Acetylation 875
Sumoylation 875
RNA Toxicity in the Polyglutamine Repeat Diseases? 875
Gene Silencing is a Promising Therapy for Polyglutamine Repeat Disease 875
RNA interference knock-down and antisense oligonucleotide knock-down: two approaches 875
Indiscriminate gene silencing 876
Allele-specific silencing 876
References 878
49. Neurotransmitters and Disorders of the Basal Ganglia 881
Anatomy and Physiology of the Basal Ganglia 881
The basal ganglia are components of larger circuits 881
Involvement of the basal ganglia in movement control 882
Multiple neurotransmitter systems are found in the basal ganglia 882
GABA 882
Glutamate 883
Acetylcholine 883
Dopamine 884
Dopamine–acetylcholine balance 885
Adenosine, cannabinoid and neuropeptides function in the basal ganglia 885
Disorders that Involve Basal Ganglia Dysfunction 886
Parkinson’s disease is a hypokinetic movement disorder 886
Pathology 886
Etiology 886
Animal models 887
Pathophysiology 887
Symptomatic drug treatment of PD 888
Surgical therapy 889
Neuroprotective treatment of PD 889
Huntington’s disease is a hyperkinetic movement disorder 890
Genetic and molecular aspects 890
Animal models 890
Treatment 890
Dystonia is a disorder with involuntary movements 891
Etiology and classification 891
Pathophysiology 892
Treatment 892
Neuropsychiatric disorders 892
Drugs affecting the basal ganglia 893
Dopamine depleting agents 893
Dopamine receptor blocking agents 893
Tardive syndromes 893
Conclusion 893
References 895
50. Molecular Basis of Prion Diseases 897
Introduction 898
Prion Diseases are Biologically Unique 898
Discovery of the prion protein 898
Prion protein is encoded by the host 898
Aberrant metabolism of the prion protein is the central feature of prion disease 898
Animal Prion Diseases 898
Scrapie and BSE 898
Other animal prion diseases 899
Human Prion Diseases 899
Human prion disease most commonly presents itself sporadically 899
Pathogenic mutations in the prion protein gene cause inherited prion disease 899
Acquired human prion diseases include kuru and variant CJD 900
Prion protein polymorphism contributes genetic susceptibility to prion disease 900
Human prion diseases are clinically heterogeneous 900
Prion Disease Pathology and Pathogenesis 901
Peripheral pathogenesis involves the lymphoreticular system 901
Prion disease produces characteristic pathology in the central nervous system 901
The Protein-Only Hypothesis of Prion Propagation 902
Prion propagation involves conversion of PrPC to PrPSc 902
Characterization of PrPC 902
PrPC has a predominantly alpha-helical conformation 902
Reverse genetics approaches to studying PrPC 903
The function of PrPC remains unknown 903
PrP knockout mice have subtle abnormalities 903
Characterization of PrPSc 904
PrPSc has a predominantly beta-sheet conformation 904
Prion structure remains unknown 904
In vitro generation of alternative PrP conformations and prion infectivity 905
The Molecular Basis of Prion Strain Diversity 905
Prion strain diversity appears to be encoded by PrP itself 905
Distinct PrPSc types are seen in human prion disease 905
Difficulties in defining human prion strains 906
Prion Transmission Barriers 907
Prion transmission between species is limited by a barrier 907
Both PrP sequence and prion strain type influence prion transmission barriers 907
A conformational selection model of prion transmission barriers 907
Subclinical forms of prion disease pose a risk to public health 907
The mechanism of prion-mediated neurodegeneration is unknown 908
Future Perspectives 908
References 909
VII. SENSORY TRANSDUCTION 912
51. Molecular Biology of Vision 914
Structure and Development of the Visual System 914
The visual system is composed of unique structures optimized for collection, detection and processing of visual information 914
The retina is composed of highly organized neuronal sublayers 915
The ganglion cell axons of the optic nerve carry visual signals from the retina to the brain 915
The eye develops as an outcropping of the developing brain 916
Photoreceptors and Phototransduction 917
Photoreceptors are polarized cells, with specialized primary cilia, outer segments, devoted to phototransduction 917
Phototransduction consists of a highly amplified cascade of light-triggered changes in protein conformation, and changes in interactions of proteins with one another and with… 917
Recovery of the dark current after light stimulation is a multistep process mediated by Ca2+ and proteins exerting negative regulation 919
Cone phototransduction uses mechanisms and molecules similar to those in rods, but is optimized for speed rather than sensitivity 920
Signaling Downstream of Photoreceptors 922
Secondary neurons respond to changes in glutamate release by rods and cones 922
ON and OFF bipolar cells use different types of receptors and response mechanisms 922
Cone bipolar cells signal to ganglion cells, and rod bipolar cells signal to aii amacrine cells 922
Recycling of Phototransduction Molecules 923
Rhodopsin regeneration requires a complex series of enzyme-catalyzed reactions in photoreceptors and RPE 923
Cones use a visual cycle distinct from that of rods to regenerate pigments 924
Retinal pigemented epithelial (RPE) cells promote disk membrane turnover by phagocytosis 924
Retinal Neurodegeneration 924
Defects in genes essential for functions of photoreceptors cause retinal degeneration 924
Age-related macular degeneration is emerging as the most common blinding disease of the developed world 924
References 925
52. Molecular Basis of Olfaction and Taste 929
Olfaction 929
The mammalian olfactory system possesses enormous discriminatory power 929
The initial events in olfaction occur in a specialized olfactory neuroepithelium 930
The identification and cloning of genes encoding odorant receptors helped to reveal organizational principles of odor coding 930
Odor discrimination involves a very large number of different odorant receptors, each responsive to a small set of odorants 931
The information generated by hundreds of different receptor types must be organized to achieve a high level of olfactory discrimination 931
Zonal Expression of Olfactory Receptors 932
Convergence of Sensory Neurons Onto a few Glomeruli in the Olfactory Bulb 932
The sensitivity of the olfactory system is likely to derive from the capacity of the olfactory transduction apparatus to effectively amplify and rapidly terminate signals 932
Odorant recognition initiates a second-messenger cascade leading to the depolarization of the neuron and the generation of action potentials 932
Negative feedback processes mediate adaptation of the olfactory transduction apparatus to prolonged or repetitive stimulation 933
Subpopulations of OSNs use alternative olfactory transduction mechanisms 934
The vomeronasal organ is an accessory chemosensing system that plays a major role in the detection of semiochemicals 935
Most vomeronasal sensory neurons are narrowly tuned to specific chemical cues, and utilize a unique mechanism of sensory transduction 936
Taste 936
Multiple senses, including taste, contribute to our total perception of food 936
Taste receptor cells are organized into taste buds 937
Sensory afferents within three cranial nerves innervate the taste buds 937
Sweet, bitter and umami taste involve G protein-coupled receptors 937
Type 1 Taste Receptors (T1Rs) Recognize Sweet and Umami Stimuli 937
Type 2 Taste Receptors (T2Rs) Mediate Responses to Bitter-Tasting Stimuli 938
T1Rs and T2Rs also Have Important Functions Outside the Gustatory System 938
Sweet, bitter and umami tasting stimuli are transduced by a G-protein–coupled signaling cascade 938
Salts and acids are transduced by direct interaction with ion channels 939
Acknowledgments 939
References 939
53. Molecular Biology of Hearing and Balance 941
General Features of Mechanotransduction 941
Mechanotransduction is of great utility for all organisms 941
Models for mechanotransduction allow comparison of mechanoreceptors from many organisms and cell types 941
Non-Vertebrate Model Systems 942
Worm mechanoreceptors use a transduction cascade that depends on epithelial sodium channels (ENaC) 943
Fly mechanoreceptors use molecules similar to those of hair cells 943
Hair Cells 943
Hair cells are the sensory cells of the auditory and vestibular systems 943
Hair cells are exposed to unusual extracellular fluids and potentials 944
Mechanical transduction depends on activation of ion channels linked to extracellular and intracellular structures 945
Some of the molecules responsible for transduction have been identified 946
Other hair cell molecules control stereocilia actin 946
Hair Cells in the Inner Ear 948
Balance: Vestibular Organs 948
Vestibular organs detect head rotation and linear acceleration 948
Hair bundles display varying morphology and physiology 948
Hearing: Cochlea 948
The cochlea detects sound and is tonotopically organized 948
High-frequency sound detection requires specialized structures and molecules 950
Cochlear hair cell mechanotransduction is similar to that of vestibular hair cells 951
Conclusions 951
References 951
54. Pain 953
Nociceptive Versus Clinical Pain 953
Nociceptors are First Responders 954
Primary sensory neurons are located in the dorsal root ganglions (DRG) of spinal nerves and the semilunar ganglions of the trigeminal nerves 954
Receptor profiles define the response modalities of nociceptors 954
Voltage-gated sodium channels determine the conduction of noxious information from the periphery to the spinal cord 955
Pain Transmission in the Spinal Cord 955
Nociceptive information enters the dorsal horn of the spinal cord 955
Signals are modulated by spinal interneurons 955
Brainstem, Thalamus and Cortex 956
Nuclei in the brainstem and thalamus, and distinct cortical areas are the major projection targets for nociceptive information 956
Brainstem nuclei play a major role in the modulation of pain 958
Opioid Analgesia 958
Cannabinoids 958
Inflammatory Pain 959
Tissue injury produces an “inflammatory soup” of signaling molecules 959
Molecular mechanisms involved in peripheral sensitization 959
Central sensitization 959
Prolonged homosynaptic facilitation 960
Neuropathic Pain 961
Paradoxically, nervous system injury may produce not only sensory loss but also chronic pain 961
Spontaneous discharges and enhanced excitability of sensory neurons 961
Allodynia signals a crossover of sensory modalities 961
Central sensitization and descending facilitation 962
Disinhibition 962
Immune response to nerve injury 963
Genetic Factors 964
Nociceptive responses and the susceptibility to clinical pain depend on genetic factors 964
Conclusion 964
Acknowledgments 964
References 965
VIII. NEURAL PROCESSING AND BEHAVIOR 968
55. Endocrine Effects on the Brain and Their Relationship to Behavior 970
Introduction 970
Behavioral Control of Hormonal Secretion 971
The hypothalamic releasing factors regulate release of the anterior pituitary trophic hormones 971
Secretion of pituitary hormones is responsive to behavior and effects of experience 971
Hormones secreted in response to behavioral signals act in turn on the brain and on other tissues 971
Classification of Hormonal Effects 972
Hormonal actions on target neurons are classified in terms of cellular mechanisms of action 972
Biochemistry of Steroid and Thyroid Hormone Actions 974
Steroid hormones are divided into six classes, based on physiological effects: estrogens, androgens, progestins, glucocorticoids, mineralocorticoids and vitamin D 974
Some steroid hormones are converted in the brain to more active products that interact with receptors 974
The Aromatization of Testosterone 975
Vitamin D 976
Genomic receptors for steroid hormones have been clearly identified in the nervous system 976
Intracellular Steroid Receptors: Properties and Topography 978
Steroid hormone receptors are phosphoproteins that have a DNA-binding domain and a steroid-binding domain 978
Estradiol 978
Progesterone 978
Androgen 979
Glucocorticoid 979
Mineralocorticoid 979
Vitamin D 979
Membrane Steroid Receptors and Signaling Pathways 979
Biochemistry of Thyroid Hormone Actions on Brain 980
Diversity of Steroid-Hormone Actions on the Brain 981
During development, steroid-hormone receptors become evident in target neurons of the brain 981
The response of neural tissue to damage involves some degree of structural plasticity, as in development 982
Activation and adaptation behaviors may be mediated by hormones 982
Enhancement of neuronal atrophy and cell loss during aging by severe and prolonged psychosocial stress are examples of allostatic load 985
SUMMARY 986
References 986
56. Learning and Memory 988
Brief History of Memory Research in Humans 988
The Penfield studies 989
Amnesia patients and the role of the temporal lobe in memory 989
Divisions of Memory 990
Declarative memory vs. procedural memory 990
Short-term memory vs. long-term memory 990
Molecular Mechanisms of Learning 990
Hebb’s rule and experimental models for synaptic plasticity 990
The NMDA receptor and LTP induction 991
Molecular mechanisms underlying the early- and late-phase expressions of LTP 992
Other forms of synaptic plasticity: Long-term depression (LTD) and NMDA receptor-independent LTP 993
Doogie mice: a smart way to validate Hebb’s rule for learning and memory 994
Molecular Mechanisms of Memory Consolidation and Storage 996
Retrograde amnesia and post-learning consolidation by the hippocampus 996
Neural Population-Level Memory Traces and Their Organizing Principles 996
In search of memory’s neural code 996
Visualizing network-level real-time memory traces 999
Identification of neural cliques as real-time memory coding units 999
General-to-specific feature-encoding neural clique assemblies 999
Concept cells in the hippocampus: nest cells and Halle Berry cells 1000
Differential reactivations within episodic cell assemblies underlying selective memory consolidation 1000
The generalization function of the hippocampus 1002
Imagination of the hippocampus 1003
References 1004
57. The Neurochemistry of Sleep and Wakefulness 1007
Sleep Phenomenology and Function: The Search for Neurochemical Substrates 1008
The daily cycle of sleep and wakefulness is one of the most fundamental aspects of human biology 1008
The functions of sleep remain enigmatic 1008
There are more neurotransmitters that promote wakefulness than those that produce sleep 1009
Development of Sleep Disorders Medicine and Sleep Neurobiology 1009
Compared to other medical specialties, sleep disorders medicine has a very short history 1009
Understanding the neurochemical regulation of sleep is essential for advancing sleep disorders medicine 1010
Monoamines 1011
Serotonin, norepinephrine and histamine are major components of the ascending reticular activating system, and each of these neurotransmitters plays a unique role in… 1011
Norepinephrine promotes arousal during normal wakefulness, and augments arousal during periods of stress and in response to psychostimulant drugs 1011
Serotonin has a biphasic effect on sleep 1011
Histamine levels are greater during wakefulness than during sleep, consistent with the fastest firing rates of histamine-containing neurons occurring during wakefulness 1012
Sleep disorders and depression are linked by monoamines 1012
Acetylcholine 1012
Acetylcholine contributes significantly to the generation of REM sleep and wakefulness 1012
Evidence that pontine cholinergic neurotransmission promotes the generation of REM sleep comes from many studies using a wide range of approaches 1013
Acetylcholine, depression, REM sleep and pain 1013
Dopamine 1013
Unlike other monoaminergic neurons, dopaminergic cells do not cease firing during REM sleep 1013
Restless legs syndrome, Parkinson’s disease and sleep 1014
Hypocretins/Orexins 1014
The discovery of hypocretins (orexins) provides an excellent example of how preclinical studies using animal models provided powerful tools for gaining mechanistic insights into… 1014
Hypocretins promote normal wakefulness 1015
Loss of hypocretinergic neurons underlies the human sleep disorder narcolepsy and contributes to other neurological disorders that show sleep… 1015
Amino Acids 1015
& #947
The effects of GABA on sleep and wakefulness vary as a function of brain region 1016
GABAergic transmission in the pontine reticular formation contributes to the regulation of sleep and wakefulness 1016
Clinical implications of GABAergic transmission for sleep 1016
Glutamate is the major excitatory neurotransmitter in the brain, yet elucidating the role of glutamate in regulating sleep and wakefulness has been challenging 1016
Effects of glutamate on sleep and wakefulness vary as a function of brain region 1017
Glutamate modulates the interaction between sleep, depression and pain 1017
Adenosine 1018
Adenosine is an endogenous sleep factor that mediates the homeostatic drive to sleep 1018
Adenosine inhibits wakefulness and promotes sleep via multiple mechanisms 1018
Adenosine is a link between opioid-induced sleep disruption and pain 1018
Conclusions and Future Directions 1019
References 1021
58. The Neurochemistry of Schizophrenia 1025
Clinical Aspects of Schizophrenia 1025
Schizophrenia is a severe, chronic disabling mental disorder 1025
Schizophrenia is characterized by three independent symptom clusters 1026
Schizophrenia is a disorder of complex genetics 1026
Current treatment of schizophrenia relies on atypical antipsychotic drugs 1026
Brain Imaging 1028
Brain imaging studies provide unequivocal evidence that schizophrenia is a brain disease 1028
Functional imaging studies have consistently shown corticolimbic abnormalities in schizophrenia 1028
Cellular and Molecular Studies 1029
The dopamine hypothesis has dominated schizophrenia research for 40 years 1029
Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia 1030
GABAergic neurons are also implicated in schizophrenia 1032
The cholinergic system has also been implicated in schizophrenia 1033
Some intracellular signal transduction molecules are reduced in schizophrenia 1033
Proteins involved in fundamental structure and function of neurons are decreased in schizophrenia 1033
Glia may play a role in schizophrenia 1033
Summary 1034
References 1035
59. The Neurochemistry of Autism 1037
Clinical Aspects of Autism Spectrum Disorders (ASDs) 1037
ASDs are defined by three independent symptom clusters 1037
Autism is heterogeneous from a behavioral, neurobiological and genetic standpoint 1038
The autism field is moving towards a more dimensional and less categorical perspective 1038
Current pharmacological treatment of autism is usually effective for only certain aspects of the symptom constellation 1039
Genetic Studies 1039
The genetics of autism are complex, heterogenetic and, in most cases, polygenetic 1039
Roles of epistasis and emergenesis are unclear 1039
Neurochemical Studies 1039
Limited postmortem brain data are available and are not definitive 1039
Dopaminergic functioning appears normal 1040
Stress response systems: basal functioning is normal, but hyperreactive in autism 1040
The serotonin system: a focus on platelet hyperserotonemia and the 5-HT2 receptor 1040
Decreased production of melatonin in autism has been reported and focuses attention on circadian processes 1041
Conclusion 1041
References 1043
60. Neurobiology of Severe Mood and Anxiety Disorders 1046
Mood Disorders 1046
Neurotransmitter and Neuropeptide Systems and the Pathophysiology of Mood Disorders 1047
Serotonergic system 1047
Noradrenergic system 1048
Dopaminergic system 1049
Cholinergic system 1049
Glutamatergic system 1049
GABAergic system 1049
Cortical-hypothalamic-pituitary-adrenal axis 1049
Thyroid axis 1049
Other neuropeptides 1050
Brain growth factors 1050
Substance P 1050
Neuroanatomical and Neuropathological Correlates of Mood Disorders 1050
Functional neuroimaging methods 1050
Stress, glucocorticoids and neuroplasticity 1051
Intracellular Signaling Pathways 1051
The G-protein–subunit/cyclic adenosine monophosphate (CAMP)–generating signaling pathway 1052
The protein kinase C signaling pathway 1052
Glycogen synthase kinase 1052
BDNF and Bcl-2 1054
Intracellular calcium signaling 1054
Anxiety Disorders 1055
The Neurochemistry of Fear and Anxiety 1055
Noradrenergic systems 1055
Serotonergic system 1056
GABAergic system 1056
CRH and stress axes 1057
Other neuropeptides 1057
Neuropeptide Y 1057
Cholecystokinin 1057
Substance P 1058
Intracellular Targets for Anxiety Disorders 1058
Future Directions and the Development of Novel Therapeutics 1058
References 1059
61. Addiction 1062
General Principles 1063
Addiction is characterized by compulsive drug use, despite severe negative consequences 1063
Many forces may drive compulsive drug use 1063
Neuronal Circuitry of Addiction 1063
Natural reinforcers and drugs of abuse increase dopamine transmission 1063
Many neuronal circuits are ultimately involved in addiction 1065
Opiates 1066
Opiates are drugs derived from opium, including morphine and heroin 1066
There are three classical opioid receptor types 1066
Opioid receptors generally mediate neuronal inhibition 1066
Chronic opiate treatment results in complex adaptations in opioid receptor signaling 1066
Opiate addiction involves multiple neuronal systems 1066
Upregulation of the cyclic AMP (cAMP) second-messenger pathway is a well-established molecular adaptation 1067
There are two main treatments for the opiate withdrawal syndrome 1068
Endogenous opioid systems are an integral part of the reward circuitry 1068
Psychomotor Stimulants 1068
This drug class includes cocaine and amphetamine derivatives 1068
Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulants 1068
Cocaine and amphetamines initiate neuronal adaptations by repeatedly elevating monoamine levels but ultimately affect glutamate and other transmitter systems 1069
Dopamine receptor transmission involves multiple signaling cascades and is altered in psychomotor stimulant addiction 1070
Cannabinoids (Marijuana) 1070
Marijuana and hashish are derivatives of the cannabis sativa plant 1070
Cannabinoid effects in the CNS are mediated by the CB1 receptor 1070
Endocannabinoids are endogenous ligands for the CB1 receptor 1071
Endocannabinoids serve as retrograde messengers that regulate synaptic plasticity 1071
There are many similarities between endogenous opioid and cannabinoid systems 1073
Nicotine 1073
Nicotine is responsible for the highly addictive properties of tobacco products 1073
Nicotine is an agonist at the nicotinic acetylcholine receptor (nAChR) 1073
The ventral tegmental area (VTA) is a critical site for nicotine action 1073
Ethanol, Sedatives and Anxiolytics 1074
Alcoholism is a chronic relapsing disorder 1074
Ethanol interacts directly with ligand-gated and voltage-gated ion channels 1074
Multiple neuronal systems contribute to the reinforcing effects of ethanol 1074
Pharmacotherapies for alcoholism are improving 1074
Barbiturates and benzodiazepines are used to treat anxiety 1075
Hallucinogens and Dissociative Drugs 1075
Hallucinogens produce an altered state of consciousness 1075
Phencyclidine (PCP) is a dissociative drug 1075
Addiction And Neuronal Plasticity Share Common Cellular Mechanisms 1076
Drugs of abuse “rewire” neuronal circuits by influencing synaptic plasticity 1076
Drugs of abuse have profound effects on transcription factors and gene expression 1076
Persistent adaptations may involve changes in the structure of dendrites and dendritic spines 1076
Acknowledgments 1077
References 1079
Glossary 1082
Index 1088