Basic Neurochemistry - Prins. of Molec., Cellular, Med. Neurobio

Cover......Page 1
BASIC NEUROCHEMISTRY: PRINCIPLES OF MOLECULAR, CELLULAR AND MEDICAL NEUROBIOLOGY......Page 4
©......Page 5
Associate Editors......Page 6
List of Boxes......Page 7
Sections......Page 10
List of Contributors......Page 11
Eighth Edition Acknowledgments and History......Page 16
Preface to the Eighth Edition......Page 17
1 Cell Biology of the Nervous System......Page 19
The classic image of a neuron includes a perikaryon, multiple dendrites and an axon......Page 20
Although neurons share common elements with other cells, each component has specialized features......Page 22
Dendrites are the afferent components of neurons......Page 25
The synapse is a specialized junctional complex by which axons and dendrites emerging from different neurons intercommunica .........Page 26
Virtually nothing can enter or leave the central nervous system parenchyma without passing through an astrocytic interphase......Page 27
The schwann cell is the myelin-producing cell of the peripheral nervous system......Page 29
The microglial cell plays a role in phagocytosis and inflammatory responses......Page 31
Homeostasis of the central nervous system (CNS) is vital to the preservation of neuronal function......Page 32
The BBB and BCSFB serve a number of key functions critical for brain function......Page 33
The lumen of the cerebral capillaries that penetrate and course through the brain tissue are enclosed by BECs interconnecte .........Page 34
Brain endothelial cells restrict the transport of many substances while permitting essential molecules access to the brain......Page 35
Lipid solubility is a key factor in determining the permeability of a substance through the BBB by passive diffusion......Page 37
ATP-binding cassette transporters (ABC) on luminal membranes of the BBB restrict brain entry of many molecules......Page 38
Acknowledgements......Page 39
References......Page 41
Cells are bounded by proteins arrayed in lipid bilayers......Page 42
Amphipathic molecules can form bilayered lamellar structures spontaneously if they have an appropriate geometry......Page 43
Membrane integral proteins have transmembrane domains that insert directly into lipid bilayers......Page 44
The fluidity of lipid bilayers permits dynamic interactions among membrane proteins......Page 45
In adult brain most cholesterol synthesis occurs in astrocytes......Page 47
The astrocytic cholesterol supply to neurons is important for neuronal development and remodeling......Page 48
The structure and roles of membrane microdomains (lipid rafts) in cell membranes are under intensive study but many aspects .........Page 49
The spectrin–ankyrin network comprises a general form of membrane-organizing cytoskeleton within which a variety of membran .........Page 50
Interaction of rafts with the cytoskeleton is suggested by the results of video microscopy......Page 51
References......Page 54
3 Membrane Transport......Page 56
Primary Active Transport (P-Type) Pumps......Page 57
The reaction mechanism of Na,K-ATPase illustrates the mechanism of P-type pumps......Page 58
The β subunits are monotopic glycoproteins and exhibit some characteristics of cell adhesion molecules......Page 59
The Na pump has associated γ subunits......Page 60
The distributions of α-subunit isoforms provide clues to their different physiological functions......Page 61
The Na,K-ATPase/Src complex functions as a signal receptor for cardiotonic steroids (CTS)......Page 62
High-resolution structural data exist for the SERCA1a Ca pump......Page 64
The Three-dimensional structures of several ABC transporters from prokaryotes have been determined......Page 66
ABCA1 translocates cholesterol and phospholipids outward across the plasma membrane......Page 67
The SLC6 subfamily of symporters for amino acid transmitters and biogenic amines is characterized by a number of shared str .........Page 68
The glutamate symporters in brain are coded by five different but closely related genes, SLC1A1–4 and SLC1A6......Page 69
Packaging neurotransmitters into presynaptic vesicles is mediated by proton-coupled antiporters......Page 70
The overall mechanism for regulation of cytosolic Ca2 is complex......Page 71
Simple diffusion of polar water molecules through hydrophobic lipid bilayers is slow......Page 72
AQP4 exists in astrocyte membranes and is coordinated with other proteins with which its function is integrated......Page 73
Facilitated diffusion of glucose across the blood–brain barrier is catalyzed by GLUT-1, -2 and -3......Page 74
HMIT is an H-coupled myoinositol symporter......Page 75
References......Page 76
4 Electrical Excitability and Ion Channels......Page 79
Excitable cells have a negative membrane potential......Page 80
Electrical signals recorded from cells are of two types: stereotyped action potentials and a variety of slow potentials......Page 81
Gating mechanisms for Na and K channels in the axolemma are voltage dependent......Page 82
Ion channels are macromolecular complexes that form aqueous pores in the lipid membrane......Page 83
Pharmacological agents acting on ion channels help define their functions......Page 84
Na channels were identified by neurotoxin labeling and their primary structures were established by cDNA cloning......Page 85
Much is known about the structural determinants of the ion selectivity filter and pore......Page 87
The fast inactivation gate is on the inside......Page 90
Three subfamilies of Ca2 channels serve distinct functions......Page 91
More ion channels are related to the NaV, CaV and KV families......Page 92
Acknowledgments......Page 93
References......Page 95
Introduction......Page 97
Brain fatty acids are long-chain carboxylic acids that may contain one or more double bonds......Page 98
Glycerolipids are derivatives of glycerol and fatty acids......Page 99
In sphingolipids, the long-chain aminodiol sphingosine serves as the lipid backbone......Page 101
Chromatography and mass spectrometry are employed to analyze and classify brain lipids......Page 105
Acetyl coenzyme A is the precursor of both cholesterol and fatty acids......Page 106
Phosphatidic acid is the precursor of all glycerolipids......Page 110
Genes for Enzymes Catalyzing Synthesis and Degradation of Lipids......Page 112
Some proteins are bound to membranes by covalently linked lipids......Page 114
References......Page 115
Introduction......Page 117
Microtubules act as both dynamic structural elements and tracks for organelle traffic......Page 118
Neuronal and glial intermediate filaments provide support for neuronal and glial morphologies......Page 122
Actin microfilaments and the membrane cytoskeleton play critical roles in neuronal growth and secretion......Page 124
A dynamic neuronal cytoskeleton provides for specialized functions in different regions of the neuron......Page 126
Both the composition and organization of cytoskeletal elements in axons and dendrites become specialized early in different .........Page 127
The axonal cytoskeleton may be influenced by glia......Page 128
Alterations in the cytoskeleton are frequent hallmarks of neuropathology......Page 130
References......Page 132
7 Intracellular Trafficking......Page 135
General Mechanisms of Intracellular Membrane Trafficking in Mammalian Cells Include Both Universal and Highly Specialized P .........Page 136
Most transport vesicles bud off as coated vesicles, with a unique set of proteins decorating their cytosolic surface......Page 137
GTP-binding proteins, such as small monomeric GTPases and heterotrimeric GTPases (G proteins) facilitate membrane transport......Page 138
Dynamins are involved in pinching off of many vesicles and membrane-bounded organelles......Page 139
Removal of coat proteins is catalyzed by specific protein chaperones......Page 140
Unloading of the transport vesicle cargo to the target membrane occurs by membrane fusion......Page 141
Historically, endoplasmic reticulum has been classified as rough or smooth, based on the presence (RER) or absence (SER) of .........Page 142
Biosynthetic and secretory cargo leaving the ER is packaged in COPII-coated vesicles for delivery to the Golgi complex......Page 143
Processing of proteins in the Golgi complex includes sorting and glycosylation of membrane proteins and secretory proteins......Page 145
Proteins and lipids move through Golgi cisternae from the cis to the trans direction......Page 146
Plasma membrane proteins are sorted to their final destinations at the trans-Golgi network......Page 147
Both constitutive and regulated neuroendocrine secretion pathways exist in cells of the nervous system......Page 148
Secretory vesicle biogenesis requires completion of a characteristic sequence of steps before vesicles are competent for se .........Page 150
Endocytosis for degradation of macromolecules and uptake of nutrients involves phagocytosis, pinocytosis and autophagy......Page 151
Retrieval of membrane components in the secretory pathway through receptor-mediated endocytosis (RME) is a clathrin-coat-de .........Page 153
In a simplistic model, the exocytosis step of neurotransmission takes place in at least three major different steps......Page 155
Many years have passed since the concept of synaptic vesicle recycling was introduced in the early 1970s, but details of th .........Page 158
References......Page 160
Introduction......Page 162
The size and extent of many neurons presents a special set of challenges......Page 163
Fast and slow components of axonal transport differ in both their constituents and their rates......Page 164
Newly synthesized membrane and secretory proteins destined for the axon travel by fast anterograde transport......Page 167
Passage through the golgi apparatus is obligatory for most proteins destined for fast axonal transport......Page 168
Retrograde transport returns trophic factors, exogenous material, and old membrane constituents to the cell body......Page 169
Molecular sorting mechanisms ensure delivery of proteins to discrete membrane compartments......Page 170
Axonal growth and regeneration are limited by rates of slow axonal transport......Page 171
Molecular Motors: Kinesin, Dynein and Myosin......Page 172
Kinesins mediate anterograde fast axonal transport in a variety of cell types......Page 173
Multiple members of the kinesin superfamily are expressed in the nervous system......Page 174
Cytoplasmic dyneins have multiple roles in the neuron......Page 175
Matching motors to physiological functions may be difficult......Page 176
AXONAL Transport and Neuropathology......Page 177
References......Page 178
Overview......Page 181
Cell adhesion molecules of the immunoglobulin superfamily (IgCAMs) represent a diverse group of proteins......Page 182
IgCAMs signal to the cytoplasm......Page 184
Cadherins are involved in multiple processes in the nervous system......Page 185
Integrins are the major cell surface receptors responsible for cell adhesion to extracellular matrix (ECM) proteins......Page 186
Integrins signal in an inside-out and outside-in fashion......Page 188
Integrins regulate myelination......Page 189
Various cell adhesion molecules cooperatively regulate the formation of interneuronal synapses in the CNS......Page 191
Integrin-cadherin cross-talk regulates neurite outgrowth......Page 193
References......Page 194
Myelin facilitates conduction......Page 196
Myelin has a characteristic ultrastructure......Page 197
Nodes of Ranvier......Page 198
Myelin is an extension of a cell membrane......Page 200
The composition of myelin is well characterized because it can be isolated in high yield and purity by subcellular fraction .........Page 201
Central nervous system myelin is enriched in certain lipids......Page 202
Peripheral and central nervous system myelin lipids are qualitatively similar......Page 203
Proteolipid protein......Page 204
Myelin basic proteins......Page 205
2:3-cyclic nucleotide 3-phosphodiesterase......Page 206
Myelin-associated glycoprotein (MAG) and other glycoproteins of CNS myelin......Page 207
Peripheral myelin protein-22......Page 208
Myelin-associated glycoprotein......Page 209
Tetraspan proteins......Page 210
Enzymes associated with myelin......Page 211
References......Page 213
11 Energy Metabolism of the Brain......Page 216
Processes related to signaling require a larger proportion of energy than do ‘basic’ cellular functions......Page 217
Function-derived signals arising from metabolism are used for brain imaging......Page 218
Endothelial cells of the blood–brain barrier and brain cells have specific transporters for the uptake of glucose and monoc .........Page 219
The transporters and pathways of metabolism change during development......Page 220
Both excitatory and inhibitory neuronal signals utilize energy derived from metabolism......Page 221
Glucose is the main obligatory substrate for energy metabolism in adult brain......Page 222
Regulation of brain hexokinase......Page 223
Glycolysis produces ATP, pyruvate for mitochondrial metabolism, and precursors for amino acids and complex carbohydrates......Page 224
Glycogen is Actively Synthesized and Degraded in Astrocytes......Page 225
The malate–aspartate shuttle is the most important pathway for transferring reducing equivalents from the cytosol to the mi .........Page 226
Lactate is formed in brain under many conditions......Page 227
Lactate can serve as fuel for brain cells under various conditions......Page 230
The TCA (citric acid) cycle is multifunctional......Page 231
ATP production in brain is highly regulated......Page 233
Acetyl-coenzyme A formed from glucose is the precursor for acetylcholine in neurons......Page 234
Other substrates (e.g., glutamate, glutamine, lactate, fatty acids, and ketone bodies) can provide energy for brain cells......Page 235
Glutamate participates in a number of metabolic pathways, and metabolism of glutamate and glutamine is compartmentalized......Page 236
The glutamate–glutamine cycle......Page 237
Local rates of glucose and oxygen utilization, functional brain imaging, redox state, and metabolic pathway analysis......Page 238
Carbon-13 nuclear magnetic resonance spectroscopy (NMR or MRS) for studying brain metabolism......Page 240
Cultured neurons and astrocytes are useful for studying subcellular compartmentation and identifying pathways of metabolism......Page 241
References......Page 242
Chemical transmission between nerve cells involves multiple steps......Page 248
Neurotransmitter release is a highly specialized form of the secretory process that occurs in virtually all eukaryotic cell .........Page 250
The neuromuscular junction is a well-defined structure that mediates the release and postsynaptic effects of acetylcholine......Page 251
Ca2 is necessary for transmission at the neuromuscular junction and other synapses and plays a special role in exocytosis......Page 252
Presynaptic events during synaptic transmission are rapid, dynamic and interconnected......Page 254
Background......Page 258
First group......Page 259
Fourth group......Page 261
Nitric oxide acts as an intercellular signaling molecule in the central nervous system......Page 262
References......Page 269
13 Acetylcholine......Page 271
Introduction......Page 272
Choline is accumulated into synaptic terminals via a specific high-affinity transporter......Page 273
ACh is packaged into vesicles by a specific transporter and is released from neurons in a Ca2-dependent manner
......Page 274
Molecular forms of AChE......Page 275
AChE catalysis: mechanism of a nearly perfect enzyme......Page 276
The active site is at the bottom of a narrow gorge in the AChE protein......Page 277
Inhibitors of AChE have toxicological, agrochemical and clinical significance......Page 278
The nicotinic receptor was the first receptor to be characterized biochemically......Page 279
nAChRs are pentameric ligand-gated ion channels......Page 280
Agonists bind at the interface between adjacent subunits......Page 281
Neuronal nAChRs form a family of related receptors......Page 282
Transgenic mice help to reveal the physiological roles and clinical implications of nAChRs......Page 284
nAChRs and disease......Page 285
nAChRs as therapeutic targets......Page 286
Pharmacological studies were the first to indicate the presence of multiple mAChR subtypes......Page 287
Molecular cloning of the mAChR reveals five subtypes......Page 288
Muscarinic receptor subtypes couple to distinct G-proteins and activate different effector mechanisms......Page 289
Transgenic mice permit an assessment of the physiological roles of individual subtypes in vivo......Page 290
Pharmacological therapies are used to treat cholinergic disorders......Page 291
References......Page 293
Catecholamines belong to the group of transmitters called monoamines......Page 296
Tyrosine hydroxylase is the rate-limiting enzyme in catecholamine biosynthesis......Page 297
Aromatic amino acid decarboxylase (AAAD), also called DOPA decarboxylase, catalyzes the conversion of L-DOPA to dopamine......Page 298
In noradrenergic and adrenergic neurons, dopamine is further converted to norepinephrine by Dopamine-β-hydroxylase (DBH)......Page 299
The physiological actions of catecholamines are terminated by reuptake into the neuron, catabolism and diffusion......Page 301
Monoamine oxidase (MAO)......Page 303
Catechol-O-methyltransferase (COMT)......Page 304
Neuroanatomy......Page 305
Catecholamines elicit their effects by binding to cell-surface receptors......Page 306
All adrenergic receptors are GPCRs......Page 308
Repeated Antagonist Treatment......Page 310
References......Page 311
15 Serotonin......Page 313
Understanding the neuroanatomical organization of serotonergic neurons provides insight into the functions of this neurotra .........Page 314
The amino acid L-tryptophan serves as the precursor for the synthesis of 5-HT......Page 317
As with other biogenic amine transmitters, 5-HT is stored primarily in vesicles and is released by an exocytotic mechanism......Page 319
The activity of 5-HT in the synapse is terminated primarily by its reuptake into serotonergic terminals......Page 321
Acute and chronic regulation of SERT function provides mechanisms for altering synaptic 5-HT concentrations and neurotransm .........Page 322
The primary catabolic pathway for 5-HT is oxidative deamination by the enzyme monoamine oxidase......Page 323
5-HT may be involved in a wide variety of behaviors by setting the tone of brain activity in relationship to the state of b .........Page 324
5-HT modulates feeding behavior and food intake......Page 325
Pharmacological and physiological studies have contributed to the definition of the many receptor subtypes for serotonin......Page 326
The 5-HT1A receptor......Page 327
The 5-HT1B and 5-HT1D receptor subtypes......Page 329
5-HT2A receptors......Page 330
The 5-HT3 receptor......Page 331
The 5-HT4 receptor......Page 332
The 5-ht5 receptor and the 5-ht1P receptor are orphan receptors......Page 333
References......Page 334
16 Histamine......Page 336
Histaminergic fibers originate from the tuberomamillary (TM) region of the posterior hypothalamus......Page 337
Histaminergic fibers project widely to most regions of the central nervous system......Page 338
Specific enzymes control histamine synthesis and breakdown......Page 340
Neuronal histamine can be methylated outside of histaminergic nerve terminals......Page 341
H1 receptors are intronless GPCRs linked to Gq and calcium mobilization......Page 342
H1-linked intracellular messengers......Page 343
H3 receptors are a family of GPCRs produced by gene splicing and linked to Gi/o......Page 344
H3-linked intracellular messengers......Page 346
H4 receptors are very similar to H3 receptors in gene structure and signal transduction, but show limited expression in the .........Page 347
Histaminergic neurons are mutually connected with other neurotransmitter systems......Page 348
Histamine functions in the nervous system......Page 349
The H3 receptor is an attractive target for the treatment of several CNS diseases......Page 350
References......Page 352
17 Glutamate and Glutamate Receptors......Page 355
Brain Glutamate is Derived from Blood-Borne Glucose and Amino Acids that Cross the Blood–Brain Barrier......Page 356
Glutamine is an Important Immediate Precursor for Glutamate: The Glutamine Cycle......Page 357
Release of glutamate from nerve endings leads to loss of a-ketoglutarate from the tricarboxylic acid cycle......Page 358
Long-Term Potentiation or Depression of Glutamatergic Synapses May Underlie Learning......Page 359
Three Classes of Ionotropic Glutamate Receptors are Identified......Page 360
Seven functional families of ionotropic glutamate receptor subunits can be defined by structural homologies......Page 361
N-methyl-D-aspartate (NMDA) receptors have multiple regulatory sites......Page 363
Genetic regulation via splice variants and RNA editing further increases receptor heterogeneity: the flip/flop versions and .........Page 367
Glutamate Produces Excitatory Postsynaptic Potentials......Page 369
Postsynaptic mGlu receptor activation modulates ion channel activity......Page 371
Glutamate Receptors Differ in their Postsynaptic Distribution......Page 372
A major scaffolding protein of the PSD is PSD95......Page 373
Sodium-Dependent Symporters in the Plasma Membranes Clear Glutamate from the Extracellular Space......Page 374
Sodium-Dependent Glutamine Transporters in Plasma Membranes Mediate the Transfer of Glutamine from Astrocytes to Neurons......Page 375
Abnormal activation of glutamate receptors in disorders of the central nervous system......Page 376
References......Page 378
Introduction......Page 380
GABA receptors have been identified electrophysiologically and pharmacologically in all regions of the brain......Page 381
GABAB receptors are heterodimers......Page 382
A family of pentameric GABAA-receptor protein subtypes exists; these vary in their localization, and in virtually every pro .........Page 383
The GABAA receptor is the major molecular target for the action of many drugs in the brain......Page 385
The three-dimensional structures of ligand-gated ion channel receptors are being modeled successfully......Page 387
References......Page 388
Purine Release......Page 390
There are several sources of extracellular adenosine......Page 392
There are four adenosine receptor subtypes......Page 395
A2A adenosine receptors are highly expressed in the basal ganglia......Page 396
ATP-adenosine is an important glial signal......Page 397
Behavioral roles for glial-derived ATP and adenosine: respiration and sleep......Page 398
Microglia and their response to injury......Page 399
Disorders of the Nervous System: Parkinson’s Disease and A2A Antagonists......Page 400
References......Page 401
Many neuropeptides were originally identified as pituitary or gastrointestinal hormones......Page 403
Peptides can be grouped by structural and functional similarity......Page 404
The neuropeptides exhibit a few key differences from the classical neurotransmitters......Page 405
Neuropeptides are often found in neurons with conventional neurotransmitters......Page 406
Many of the enzymes involved in peptide biogenesis have been identified......Page 407
Diversity is generated by families of propeptides, alternative splicing, proteolytic processing and post-translational modi .........Page 412
Most neuropeptide receptors are seven-transmembrane-domain, G-protein–coupled receptors......Page 413
Neuropeptide receptors are not confined to synaptic regions......Page 414
The study of peptidergic neurons requires a number of special tools......Page 415
Regulation of neuropeptide expression is exerted at several levels......Page 416
Mutations and knockouts of peptide-processing enzyme genes cause a myriad of physiological problems......Page 417
Enkephalin knockout mice reach adulthood and are healthy......Page 418
References......Page 419
The family of heterotrimeric G proteins is involved in transmembrane signaling in the nervous system, with certain exceptio .........Page 421
G proteins couple some neurotransmitter receptors directly to ion channels......Page 422
G proteins regulate intracellular concentrations of second messengers......Page 424
G protein βγ subunits subserve numerous functions in the cell......Page 425
The functioning of heterotrimeric G proteins is modulated by other proteins......Page 426
The best-characterized small G protein is the Ras family, a series of related proteins of 21 kDa......Page 428
G proteins can be modified by ADP-ribosylation catalyzed by certain bacterial toxins......Page 429
G proteins are implicated in the pathophysiology and treatment of disease......Page 430
References......Page 431
Biochemistry of cAMP production......Page 433
Adenylyl Cyclase 1......Page 435
Adenylyl Cyclase 4 and 7......Page 436
Models for cellular regulation of the different types of adenylyl cyclase......Page 437
Cyclic nucleotide-gated channels......Page 439
Guanylyl Cyclases......Page 440
Membrane-bound guanylyl cyclase......Page 441
Soluble guanylyl cyclases......Page 442
Functions of cGMP signaling in the brain......Page 443
Ca2/calmodulin-stimulated PDEs (PDE1)......Page 444
cGMP-regulated PDEs (PDE2, PDE3, and PDE11)......Page 445
G protein–activated phosphodiesterase in retinal phototransduction: PDE6......Page 446
PDEs regulated primarily by phosphorylation: PDE4, 5 and 10......Page 447
Spatiotemporal Integration and Regulation of Cyclic Nucleotide Signaling in Neurons......Page 448
References......Page 449
Introduction......Page 490
The three quantitatively major phosphoinositides are structurally and metabolically related......Page 491
The quantitatively minor 3-phosphoinositides are synthesized by phosphatidylinositol 3-kinase......Page 492
Phosphoinositides are dephosphorylated by phosphatases......Page 493
Phosphoinositides are cleaved by a family of phosphoinositide-specific phospholipase C (PLC) isozymes......Page 494
D-myo-inositol 1,4,5-trisphosphate [i(1,4,5)p3] is a second messenger that liberates Ca2 from the endoplasmic reticulum vi .........Page 496
Protein kinase C is activated by the second messenger diacylglycerol......Page 497
Membrane trafficking......Page 499
Regulation of ion channel activity......Page 500
References......Page 501
The Calcium Signal in Context......Page 478
The optical monitoring of [Ca2] relies on indicators whose fluorescence changes upon binding to calcium......Page 479
The balance between calcium efflux and influx at the plasma membrane determines [Ca2]......Page 480
Cellular Organelles and Calcium Pools......Page 481
Activation of different ER signaling pathways elicit different responses......Page 482
Mitochondria have a complex impact on Ca2 dynamics......Page 483
Electrically silent astrocytes use Ca2 as a signaling molecule......Page 484
The tripartite synapse: gliotransmitters and modulation of transmission at the synapse......Page 485
Astrocyte control of cerebral vasculature......Page 486
Conclusions......Page 487
References......Page 488
Protein Phosphorylation is a Fundamental Mechanism Regulating Cellular Functions......Page 452
Phosphorylation levels of substrate proteins are regulated by antagonistic actions of protein kinases and protein phosphata .........Page 453
Protein kinases differ in their cellular and subcellular distribution, substrate specificity and regulation......Page 455
Protein kinase C......Page 458
Calcium2/calmodulin-dependent kinases......Page 460
The MAPK cascade is a classical example of second messenger–independent protein Ser/Thr kinase signaling......Page 461
c-Jun NH2-terminal kinases......Page 462
Casein kinase 1 (CK1)......Page 463
Protein Ser/Thr Phosphatases......Page 464
Protein phosphatase 2B (PP2B)......Page 465
Common strategies used for the evaluation of neuronal functions of protein kinases and phosphatases......Page 466
Phosphorylation can influence protein function in various ways......Page 467
Cellular signals converge at the level of protein phosphorylation pathways......Page 468
Protein Phosphorylation is a Fundamental Mechanism Underlying Synaptic Plasticity and Memory Functions......Page 469
Presynaptic mechanisms regulated by protein phosphorylation......Page 470
Postsynaptic mechanisms regulated by protein phosphorylation......Page 472
Genetic neuronal disorders due to mutations in genes of protein kinases and phosphatases......Page 474
Protein phosphorylation and AD......Page 475
References......Page 476
Tyrosine Phosphorylation in the Nervous System......Page 503
Nonreceptor protein tyrosine kinases contain a catalytic domain, as well as various regulatory domains important for proper .........Page 504
Receptor protein tyrosine kinases consist of an extracellular domain, a single transmembrane domain and a cytoplasmic domai .........Page 508
RPTK Inactivation......Page 510
Protein Tyrosine Phosphatases......Page 511
Protein tyrosine phosphatases are structurally different from serine–threonine phosphatases and contain a cysteine residue  .........Page 513
Nonreceptor tyrosine phosphatases are cytoplasmic and have regulatory sequences flanking the catalytic domain......Page 514
Tyrosine phosphorylation is involved in every stage of neuronal development......Page 515
Tyrosine phosphorylation contributes to the formation of synapses in the central nervous system......Page 519
N-Methyl-d-Aspartate Receptors......Page 520
References......Page 521
The Transcriptional Process......Page 524
Histone acetylation......Page 526
Histone and DNA methylation......Page 527
Technology that has hastened the study of transcription......Page 528
NextGen sequencing to assess the cellular transcriptome......Page 530
Glucocorticoid and Mineralocorticoid Receptors as Transcription Factors......Page 531
The mechanisms of corticosteroid receptor regulation of transcription have been elucidated......Page 532
camp Regulation of Transcription......Page 534
The function of the cAMP response element–binding protein has been modeled in transgenic organisms......Page 535
Ectopic expression of transcription factors can reprogram differentiated cells to induce “stemness”......Page 537
Transcription as a Target for Drug Development......Page 538
References......Page 539
Introduction......Page 541
A dorsoventral pattern arises with signals from adjacent non-neuronal cells......Page 542
The rostrocaudal axis is specified by homeobox-containing genes......Page 543
Embryonic signaling centers organize large regions of the brain......Page 546
Reelin and notch signaling contribute to cortical layer organization......Page 547
Neuronal specification involves proneural and neurogenic gene gunctions......Page 548
The neural crest gives rise to PNS derivatives by induction......Page 549
Naturally occurring cell death eliminates cells and synapses......Page 550
Activity and Experience Shape Long-Lasting Connections......Page 551
Summary......Page 552
References......Page 553
Introduction: What is a Growth Factor?......Page 554
Nerve growth factor......Page 555
Brain-derived neurotrophic factor......Page 556
Neurotrophin 4......Page 558
Neurotrophin Receptors......Page 559
The p75 neurotrophin receptor (p75NTR)......Page 560
Glial Cell line–Derived Neurotrophic Factor (GDNF)......Page 561
GFL Receptors......Page 562
Neurotrophic Cytokines......Page 563
References......Page 565
Stem Cells are Multipotent and Self-Renewing......Page 566
Neural Stem Cells Contribute to Neurons and Glia During Normal Development......Page 567
The peripheral nervous system (PNS) is derived from neural crest stem cells......Page 568
The neurosphere functional assay......Page 569
Induced pluripotent stem cells, reprogramming and directed differentiation......Page 570
Stem cells to replace depleted neurochemicals: Parkinson’s disease......Page 571
Stem cells for cell replacement therapy: myelin......Page 572
Stem cells as a source of growth factors and guidance cues......Page 573
Common challenges for stem cell therapy in the nervous system......Page 574
References......Page 575
Introduction......Page 577
Much early work was possible because of in vitro analysis of the oligodendrocyte cell lineage......Page 578
The discovery of several transcription factors that are expressed at early stages of oligodendrocyte specification and diff .........Page 579
A number of transcriptional and epigenetic regulators control oligodendrocyte progenitor cell differentiation into premyeli .........Page 580
Extensive recent research has focused on identifying the axonal signals that regulate myelination......Page 582
Sorting and transport of lipids and proteins takes place during myelin assembly......Page 583
Rodent mutants of myelination have been investigated since the 1950s......Page 584
There are signal transduction systems in myelin sheaths......Page 585
Leukodystrophies define a number of genetic disorders that impact CNS myelination (dysmyelination) or myelin maintenance on .........Page 586
Peripheral nerve regeneration has been studied extensively......Page 587
References......Page 588
Introduction......Page 590
The molecular and cellular events during Wallerian degeneration in the PNS transform the damaged nerve into an environment  .........Page 591
Both Schwann cells and basal lamina are required for axonal regeneration to proceed......Page 592
Central nervous system myelin contains molecules that inhibit neurite growth......Page 593
Nogo-A is a potent inhibitor of neurite growth and blocks axonal regeneration in the central nervous system......Page 594
Nogo gene is a member of the reticulon superfamily......Page 595
Additional myelin components have growth-inhibitory activity......Page 596
Axon growth is inhibited by the glial scar......Page 597
Neonatal brain damage results in compensatory plasticity......Page 598
Compensatory plasticity and functional recovery can be enhanced in the injured adult central nervous system through blockad .........Page 599
Summary......Page 600
References......Page 601
Definition: What is neuroimmunology?......Page 603
Relevance: A real-world example......Page 604
Antigen presentation by major histocompatibility-complex–expressing cells is required to activate T-cells......Page 605
Choosing between immune tolerance and inflammation......Page 607
Functional consequences of lymphoid tissue innervation......Page 608
Immune Privilege Is Not Immune Isolation: The CNS as an Immune-Active Organ......Page 609
Leukocyte migration into the CNS parenchyma is a two-step process......Page 610
Distinguishing CNS-resident microglia from CNS-infiltrating macrophages......Page 611
The CNS microenvironment actively regulates the phenotype of microglia and infiltrating immune cells......Page 612
Immune-Regulated Changes in Neuronal Function and Mammalian Behavior......Page 613
References......Page 614
Neuroinflammation: Introduction......Page 616
The role of microglia in neuroinflammation......Page 617
Receptors in microglia......Page 618
Protein Aggregation......Page 619
Initiation of inflammation: prostaglandin and leukotriene pathways......Page 620
The inflammasome......Page 622
Neuroprotective Signaling Circuits......Page 623
References......Page 624
Brain Responses to Ischemia......Page 627
Focal cerebral ischemia......Page 628
Global cerebral ischemia......Page 629
Ca2 overloading in the ischemic injury......Page 633
NMDA receptors, brain function and cell death......Page 634
Reactive oxygen species contribute to the injury......Page 635
Brain antioxidants contribute to the protection of brain from ischemia–reperfusion injury......Page 636
Metalloproteinases during the neurovascular unit disruption......Page 637
Inflammatory mediators and anti-inflammatory regulation......Page 638
Apoptotic signaling......Page 639
Docosanoids and penumbra protection......Page 641
Potential Therapeutic Strategies for Acute Ischemic Stroke......Page 644
References......Page 646
36 Lipid Mediators: Eicosanoids, Docosanoids and Platelet-Activating Factor......Page 649
Excitable membranes maintain and rapidly modulate substantial transmembrane ion gradients in response to stimuli......Page 650
Mammalian phospholipids generally contain polyunsaturated fatty acyl chains almost exclusively esterified to the second car .........Page 651
There are high-affinity receptors that bind secretory phospholipases A2......Page 653
Prostaglandins are very rapidly released from neurons and glial cells......Page 654
Platelet-Activating Factor......Page 655
Platelet-activating factor is a very potent and short-lived lipid messenger......Page 656
Cyclooxygenase-2 participates in aberrant synaptic plasticity during epileptogenesis......Page 658
15-Lipoxygenase catalyzes the oxygenation of arachidonic acid at the 15-position to Form 15-HpETE......Page 659
Free arachidonic acid, along with diacylglycerols and free docosahexaenoic acid, are products of membrane lipid breakdown a .........Page 660
Free fatty acid release during cerebral ischemia is a complex process that includes the activation of signaling cascades......Page 661
Rhodopsin in photoreceptors is immersed in a lipid environment highly enriched in phospholipids containing docosahexaenoic  .........Page 662
Knowledge of the significance of lipid signaling in the nervous system is being expanded by advances in experimental approa .........Page 663
Arachidonic acid is widely implicated in signaling in brain, and research continues toward understanding the release of thi .........Page 664
References......Page 666
During embryonic and postnatal development, and throughout adult life, many cells in the nervous system die......Page 669
Adaptive apoptosis occurs in the developing and adult nervous system......Page 670
Apoptosis occurs in acute neurological insults......Page 671
Apoptosis occurs in neurodegenerative disorders......Page 673
Oxidative and metabolic stress......Page 674
Once apoptosis is triggered, a stereotyped sequence of premitochondrial events occurs that executes the cell death process......Page 675
Neurotrophic factors, cytokines and cell adhesion molecules......Page 676
Antioxidants and calcium-stabilizing proteins......Page 677
Energy failure/ischemia......Page 678
 TARGETING Apoptosis and Necrosis in Neurological DISORDERS......Page 679
References......Page 681
Introduction......Page 683
The inherited neuropathies are commonly referred to as Charcot-Marie-Tooth disorders (CMT) or hereditary motor and sensory  .........Page 684
An autoimmune attack on the PNS can manifest in various disease forms that include but are not limited to Guillain-Barré sy .........Page 688
Axon Degeneration and Protection......Page 691
References......Page 692
39 Diseases Involving Myelin......Page 695
Diagnosis......Page 696
Gray matter lesions......Page 697
Biochemistry......Page 698
Environmental factors......Page 699
Viral models......Page 700
Some human peripheral neuropathies involving demyelination are immune mediated......Page 701
Guillain–Barré syndrome......Page 702
Lysosomal storage diseases......Page 703
Myelin formation and stability are affected by a variety of other etiologies including developmental insults, nutritional d .........Page 705
The capacity for remyelination depends upon the presence of receptive axons and sufficient myelin-forming cells......Page 706
References......Page 707
Terminology and Classification......Page 727
Disrupting the delicate balance of inhibitory and excitatory synaptic transmission can trigger the disordered, synchronous  .........Page 728
Normally the dentate granule cells of hippocampus limit excessive activation of their targets, the CA3 pyramidal cells......Page 730
Epileptogenesis is the process by which a normal brain becomes epileptic......Page 731
Identifying molecular mechanisms of epileptogenesis will provide new targets for developing small molecules to prevent epil .........Page 732
Other antiseizure drugs enhance GABA-mediated synaptic inhibition......Page 733
Other antiseizure drugs regulate a subset of voltage-gated calcium currents......Page 734
Many forms of epilepsy have genetic determinants......Page 735
Some spontaneous and some engineered mutations of mice result in epilepsy......Page 737
References......Page 739
Genetic Aspects of Common Neurodegenerative Diseases......Page 709
Apolipoprotein E in late-onset AD......Page 711
Genome-wide screening in late-onset AD......Page 712
Autosomal-recessive forms of PD......Page 713
Candidate-gene studies and genome-wide screening in PD......Page 714
The genetics of DLB shows similarities with both PD and AD......Page 715
Genetic determinants of tau-negative FTLD......Page 716
Familial ALS......Page 717
Huntington’s disease (HD)......Page 719
PRNP mutations are causal and influence disease progression......Page 720
Concluding Remarks......Page 721
References......Page 723
42 Disorders of Amino Acid Metabolism......Page 741
Untreated aminoacidurias can cause brain damage in many ways, often through impairing brain energy metabolism......Page 742
An imbalance of amino acids in the blood often alters the rate of transport of these compounds into the brain, thereby affe .........Page 744
Maple syrup urine disease involves a congenital failure to oxidize the three branched-chain amino acids......Page 746
Phenylketonuria usually is caused by a congenital deficiency of phenylalanine hydroxylase......Page 747
Nonketotic hyperglycinemia causes a severe seizure disorder and profound brain damage......Page 748
The transsulfuration pathway is the major route for the metabolism of the sulfur-containing amino acids......Page 749
Prognosis is more favorable in the pyridoxine-responsive patients......Page 751
Cobalamin-c disease: remethylation of homocysteine to methionine also requires an ‘activated’ form of vitamin B12......Page 752
The urea cycle is essential for the detoxification of ammonia......Page 753
Citrullinemia......Page 754
Successful management of urea cycle defects involves a low-protein diet to minimize ammonia production as well as medicatio .........Page 755
Congenital defects in the metabolism of γ-aminobutyric acid have been described......Page 756
References......Page 757
The cell contains specialized organelles for the recycling of waste material: the lysosomes......Page 759
Deficiency of a lysosomal enzyme causes the blockage of the corresponding metabolic pathway, leading to the accumulation of .........Page 760
Gaucher disease......Page 761
Metachromatic leukodystrophy (MLD)......Page 762
GM2 gangliosidoses (Tay–Sachs disease; Sandhoff disease and GM2 activator deficiency)......Page 763
Peroxisomes are specialized organelles for metabolism of oxygen peroxide and of various lipids......Page 764
Defects of single peroxisomal enzymes......Page 765
Diseases of Carbohydrate and Fatty Acid Metabolism......Page 766
Genetic defects of phosphorylase b kinase (PHK)......Page 767
Other glycolytic defects involving PFK, PGK, PGAM, and LDH have clinical and pathological features similar to McArdle disea .........Page 768
Acid maltase deficiency (AMD) (glycogenosis type II)......Page 770
Carnitine deficiency......Page 771
The impairment of energy production, be it from carbohydrate or lipids, is expected to lead to common consequences and resu .........Page 772
Branching enzyme deficiency......Page 774
Pyruvate carboxylase deficiency......Page 775
Mitochondrial dysfunction produces syndromes involving muscle and the central nervous system......Page 776
Mitochondrial DNA is inherited maternally......Page 777
Defects of nuclear DNA......Page 778
Defects of substrate utilization......Page 779
Abnormalities of the respiratory chain: defects of complex I......Page 780
Abnormalities of the respiratory chain: defects of complex IV......Page 781
Abnormalities of the respiratory chain: defects of complex V......Page 782
References......Page 783
Nerve and muscle communicate through neuromuscular junctions......Page 787
The fidelity of signal transmission relies on the orchestration of innumerable stochastic molecular events......Page 789
Myofibrils are designed and positioned to produce movement and force......Page 790
Calcium couples muscle membrane excitation to filament contraction......Page 791
AChR Deficiency......Page 793
Mutations of the sodium channel cause hyperkalemic periodic paralysis and paramyotonia congenital......Page 794
Ribonuclear inclusions are responsible for the multiple manifestations of myotonic dystrophy......Page 795
Malignant hyperthermia caused by mutant ryanodine receptor calcium release channels......Page 796
Antibodies against MuSK mimic myasthenia gravis......Page 797
Potassium channel antibodies in Isaac syndrome cause neuromyotonia......Page 798
Bacterial botulinum toxin blocks presynaptic ACh release......Page 799
Snake, scorpion, spider, fish and snail peptide venoms act on multiple molecular targets at the neuromuscular junction......Page 800
Electrolyte imbalances alter the voltage sensitivity of muscle ion channels......Page 802
References......Page 803
Amyotrophic Lateral Sclerosis Is the Most Common Adult-Onset Motor Neuron Disease......Page 805
The disease is characterized clinically by weakness, muscle atrophy and spasticity affecting both upper and lower motor neu .........Page 806
Angiogenic factors may be linked to ALS......Page 807
ALS is linked to two genes involved in RNA metabolism: TDP-43 and FUS......Page 808
Mutations in OPTN were identified in several japanese patients with ALS......Page 809
Hereditary canine spinal muscular atrophy (HCSMA) is a naturally occurring mutation that produces motor neuron disease......Page 810
Lines of mice harboring other mutant genes may also develop an ALS-like phenotype......Page 811
Expression of GLT1 is implicated as a possible cofactor......Page 812
Available Genetic Mouse Models Will Aid in Discovering Disease Mechanisms and Novel Means of Therapy......Page 813
References......Page 815
Alzheimer’s Disease is the Most Prevalent Neurodegenerative Disease of the Elderly......Page 819
Advances in laboratory measurements and imaging are of value in establishing the diagnosis of AD......Page 820
Multiple neurotransmitter circuits and brain networks are damaged in AD......Page 821
Neurofibrillary tangles (NFT), another characteristic feature of AD, are composed of intracellular bundles of paired helica .........Page 822
Aspartyl proteases carry out the β- and g-secretase cleavages of APP to generate Aβ peptides......Page 823
Transgenic strategies have been used to create models of Aβ amyloidosis and tauopathies......Page 824
Gene targeting approaches have identified and validated targets for therapy......Page 825
Transgenic mouse models are being used to test a variety of novel therapies......Page 826
Conclusions......Page 827
References......Page 829
Introduction......Page 833
Synucleins are lipid-binding proteins......Page 834
Lewy body filaments are made of α-synuclein......Page 835
Other genes are implicated in Parkinson’s disease......Page 836
Rodents and primates......Page 837
Six tau isoforms are expressed in adult human brain......Page 838
Filamentous tau is hyperphosphorylated......Page 839
MAPT mutations are exonic or intronic......Page 840
Relevance for Other Tauopathies......Page 841
Rodents and fish......Page 842
Flies, worms and yeasts......Page 844
References......Page 845
CAG repeat expansions are responsible for nine inherited neurodegenerative disorders......Page 864
Polyglutamine disease proteins form aggregates visible at the light microscope level......Page 865
Are polyglutamine tracts substrates for the ubiquitin-proteasome system and autophagy pathways?......Page 866
Autophagy pathway involvement in polyglutamine neurodegeneration......Page 867
Phosphorylation......Page 869
RNA interference knock-down and antisense oligonucleotide knock-down: two approaches......Page 870
Allele-specific silencing......Page 871
References......Page 873
The basal ganglia are components of larger circuits......Page 848
GABA......Page 849
Acetylcholine......Page 850
Dopamine......Page 851
Adenosine, cannabinoid and neuropeptides function in the basal ganglia......Page 852
Etiology......Page 853
Pathophysiology......Page 854
Symptomatic drug treatment of PD......Page 855
Neuroprotective treatment of PD......Page 856
Treatment......Page 857
Etiology and classification......Page 858
Neuropsychiatric disorders......Page 859
Conclusion......Page 860
References......Page 862
50 Molecular Basis of Prion Diseases......Page 903
Scrapie and BSE......Page 904
Pathogenic mutations in the prion protein gene cause inherited prion disease......Page 905
Human prion diseases are clinically heterogeneous......Page 906
Prion disease produces characteristic pathology in the central nervous system......Page 907
PrPC has a predominantly alpha-helical conformation......Page 908
PrP knockout mice have subtle abnormalities......Page 909
Prion structure remains unknown......Page 910
Distinct PrPSc types are seen in human prion disease......Page 911
Difficulties in defining human prion strains......Page 912
Subclinical forms of prion disease pose a risk to public health......Page 913
Future Perspectives......Page 914
References......Page 915
The visual system is composed of unique structures optimized for collection, detection and processing of visual information......Page 876
The ganglion cell axons of the optic nerve carry visual signals from the retina to the brain......Page 877
The eye develops as an outcropping of the developing brain......Page 878
Phototransduction consists of a highly amplified cascade of light-triggered changes in protein conformation, and changes in .........Page 879
Recovery of the dark current after light stimulation is a multistep process mediated by Ca2 and proteins exerting negative .........Page 881
Cone phototransduction uses mechanisms and molecules similar to those in rods, but is optimized for speed rather than sensi .........Page 882
Cone bipolar cells signal to ganglion cells, and rod bipolar cells signal to aii amacrine cells......Page 884
Rhodopsin regeneration requires a complex series of enzyme-catalyzed reactions in photoreceptors and RPE......Page 885
Age-related macular degeneration is emerging as the most common blinding disease of the developed world......Page 886
References......Page 887
The mammalian olfactory system possesses enormous discriminatory power......Page 891
The identification and cloning of genes encoding odorant receptors helped to reveal organizational principles of odor codin .........Page 892
The information generated by hundreds of different receptor types must be organized to achieve a high level of olfactory di .........Page 893
Odorant recognition initiates a second-messenger cascade leading to the depolarization of the neuron and the generation of  .........Page 894
Negative feedback processes mediate adaptation of the olfactory transduction apparatus to prolonged or repetitive stimulati .........Page 895
Subpopulations of OSNs use alternative olfactory transduction mechanisms......Page 896
The vomeronasal organ is an accessory chemosensing system that plays a major role in the detection of semiochemicals......Page 897
Multiple senses, including taste, contribute to our total perception of food......Page 898
Type 1 Taste Receptors (T1Rs) Recognize Sweet and Umami Stimuli......Page 899
Sweet, bitter and umami tasting stimuli are transduced by a G-protein–coupled signaling cascade......Page 900
References......Page 901
Models for mechanotransduction allow comparison of mechanoreceptors from many organisms and cell types......Page 917
Non-Vertebrate Model Systems......Page 918
Hair cells are the sensory cells of the auditory and vestibular systems......Page 919
Hair cells are exposed to unusual extracellular fluids and potentials......Page 920
Mechanical transduction depends on activation of ion channels linked to extracellular and intracellular structures......Page 921
Other hair cell molecules control stereocilia actin......Page 922
The cochlea detects sound and is tonotopically organized......Page 924
High-frequency sound detection requires specialized structures and molecules......Page 926
References......Page 927
Nociceptive Versus Clinical Pain......Page 966
Receptor profiles define the response modalities of nociceptors......Page 967
Signals are modulated by spinal interneurons......Page 968
Nuclei in the brainstem and thalamus, and distinct cortical areas are the major projection targets for nociceptive informat .........Page 969
Cannabinoids......Page 971
Central sensitization......Page 972
Prolonged homosynaptic facilitation......Page 973
Allodynia signals a crossover of sensory modalities......Page 974
Disinhibition......Page 975
Immune response to nerve injury......Page 976
Acknowledgments......Page 977
References......Page 978
Introduction......Page 929
Hormones secreted in response to behavioral signals act in turn on the brain and on other tissues......Page 930
Hormonal actions on target neurons are classified in terms of cellular mechanisms of action......Page 931
Some steroid hormones are converted in the brain to more active products that interact with receptors......Page 933
The Aromatization of Testosterone......Page 934
Genomic receptors for steroid hormones have been clearly identified in the nervous system......Page 935
Progesterone......Page 937
Membrane Steroid Receptors and Signaling Pathways......Page 938
Biochemistry of Thyroid Hormone Actions on Brain......Page 939
During development, steroid-hormone receptors become evident in target neurons of the brain......Page 940
Activation and adaptation behaviors may be mediated by hormones......Page 941
Enhancement of neuronal atrophy and cell loss during aging by severe and prolonged psychosocial stress are examples of allo .........Page 944
References......Page 945
Brief History of Memory Research in Humans......Page 947
Amnesia patients and the role of the temporal lobe in memory......Page 948
Hebb’s rule and experimental models for synaptic plasticity......Page 949
The NMDA receptor and LTP induction......Page 950
Molecular mechanisms underlying the early- and late-phase expressions of LTP......Page 951
Other forms of synaptic plasticity: Long-term depression (LTD) and NMDA receptor-independent LTP......Page 952
Doogie mice: a smart way to validate Hebb’s rule for learning and memory......Page 953
In search of memory’s neural code......Page 955
General-to-specific feature-encoding neural clique assemblies......Page 958
Differential reactivations within episodic cell assemblies underlying selective memory consolidation......Page 959
The generalization function of the hippocampus......Page 961
Imagination of the hippocampus......Page 962
References......Page 963
57 The Neurochemistry of Sleep and Wakefulness......Page 980
The functions of sleep remain enigmatic......Page 981
Compared to other medical specialties, sleep disorders medicine has a very short history......Page 982
Understanding the neurochemical regulation of sleep is essential for advancing sleep disorders medicine......Page 983
Serotonin has a biphasic effect on sleep......Page 984
Acetylcholine contributes significantly to the generation of REM sleep and wakefulness......Page 985
Unlike other monoaminergic neurons, dopaminergic cells do not cease firing during REM sleep......Page 986
The discovery of hypocretins (orexins) provides an excellent example of how preclinical studies using animal models provide .........Page 987
γ-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the brain, and drugs that enhance transmission at GA .........Page 988
Glutamate is the major excitatory neurotransmitter in the brain, yet elucidating the role of glutamate in regulating sleep  .........Page 989
Glutamate modulates the interaction between sleep, depression and pain......Page 990
Adenosine is a link between opioid-induced sleep disruption and pain......Page 991
Conclusions and Future Directions......Page 992
References......Page 994
Schizophrenia is a severe, chronic disabling mental disorder......Page 998
Current treatment of schizophrenia relies on atypical antipsychotic drugs......Page 999
Functional imaging studies have consistently shown corticolimbic abnormalities in schizophrenia......Page 1001
The dopamine hypothesis has dominated schizophrenia research for 40 years......Page 1002
Hypofunction of NMDA receptors may contribute to the endophenotype of schizophrenia......Page 1003
GABAergic neurons are also implicated in schizophrenia......Page 1005
Glia may play a role in schizophrenia......Page 1006
Summary......Page 1007
References......Page 1008
ASDs are defined by three independent symptom clusters......Page 1010
The autism field is moving towards a more dimensional and less categorical perspective......Page 1011
Limited postmortem brain data are available and are not definitive......Page 1012
The serotonin system: a focus on platelet hyperserotonemia and the 5-HT2 receptor......Page 1013
Conclusion......Page 1014
References......Page 1016
Mood Disorders......Page 1019
Serotonergic system......Page 1020
Noradrenergic system......Page 1021
Thyroid axis......Page 1022
Functional neuroimaging methods......Page 1023
Intracellular Signaling Pathways......Page 1024
Glycogen synthase kinase......Page 1025
Intracellular calcium signaling......Page 1027
Noradrenergic systems......Page 1028
GABAergic system......Page 1029
Cholecystokinin......Page 1030
Future Directions and the Development of Novel Therapeutics......Page 1031
References......Page 1032
61 Addiction......Page 1035
Natural reinforcers and drugs of abuse increase dopamine transmission......Page 1036
Many neuronal circuits are ultimately involved in addiction......Page 1038
Opiate addiction involves multiple neuronal systems......Page 1039
Upregulation of the cyclic AMP (cAMP) second-messenger pathway is a well-established molecular adaptation......Page 1040
Transporters for dopamine (DAT), serotonin (SERT) and norepinephrine (NET) are the initial targets for psychomotor stimulan .........Page 1041
Cocaine and amphetamines initiate neuronal adaptations by repeatedly elevating monoamine levels but ultimately affect gluta .........Page 1042
Cannabinoid effects in the CNS are mediated by the CB1 receptor......Page 1043
Endocannabinoids serve as retrograde messengers that regulate synaptic plasticity......Page 1044
The ventral tegmental area (VTA) is a critical site for nicotine action......Page 1046
Pharmacotherapies for alcoholism are improving......Page 1047
Phencyclidine (PCP) is a dissociative drug......Page 1048
Persistent adaptations may involve changes in the structure of dendrites and dendritic spines......Page 1049
Acknowledgments......Page 1050
References......Page 1052
Glossary......Page 1054
Index......Page 1060