ElementsofMolecularNeurobiology.C.U.M.Smith Copyright2002JohnWiley&Sons,Ltd. ISBNs:0-470-84353-5(HB);0-471-56038-3(PB) Elements of Molecular Neurobiology ThirdEdition For Rosemary Always in my heart Elements of Molecular Neurobiology ThirdEdition C. U. M. 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CONTENTS Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . xi 3.4 Control of the Expression of Genetic Preface to the First Edition. . . . . . . . . . . . . xiii Information . . . . . . . . . . . . . . . . . . . 65 Preface to the Second Edition . . . . . . . . . . . xv 3.4.1 Genomic Control. . . . . . . . . . . . . 66 3.4.2 Transcriptional Control . . . . . . . . 67 1 Introductory Orientation. . . . . . . . . . . . . 1 BOX 3.2: Oncogenes, proto- 1.1 Outline of Nervous Systems . . . . . . . . 2 oncogenes and IEGs . . . . . . . . . . 69 1.2 Vertebrate Nervous Systems. . . . . . . . 4 3.4.3 Post-transcriptional Control . . . . . 73 1.3 Cells of the Nervous Systems . . . . . . . 7 3.4.4 Translational Control. . . . . . . . . . 74 1.3.1 Neurons . . . . . . . . . . . . . . . . . . . 7 3.4.5 Post-translational Control. . . . . . . 75 1.3.2 Glia . . . . . . . . . . . . . . . . . . . . . . 11 3.5 Conclusion . . . . . . . . . . . . . . . . . . . . 76 1.4 Organisation of Synapses. . . . . . . . . . 14 1.5 Organisation of Neurons in the Brain . 16 4 Molecular Evolution. . . . . . . . . . . . . . . . 77 2 The Conformation of Informational 4.1 Mutation . . . . . . . . . . . . . . . . . . . . . 79 Macromolecules . . . . . . . . . . . . . . . . . . 22 4.1.1 Point Mutations . . . . . . . . . . . . . 79 4.1.2 Proof-reading and Repair 2.1 Proteins . . . . . . . . . . . . . . . . . . . . . . 22 Mechanisms . . . . . . . . . . . . . . . . 80 2.1.1 Primary Structure . . . . . . . . . . . . 23 4.1.3 Chromosomal Mutations . . . . . . . 84 2.1.2 Secondary Structure. . . . . . . . . . . 28 4.2 Protein Evolution . . . . . . . . . . . . . . . 87 2.1.3 Tertiary Structure . . . . . . . . . . . . 35 4.2.1 Evolutionary Development of 2.1.4 Quaternary Structure. . . . . . . . . . 37 Protein Molecules and 2.1.5 Molecular Chaperones . . . . . . . . . 38 Phylogenetic Relationships . . . . . . 87 2.2 Nucleic Acids . . . . . . . . . . . . . . . . . . 39 4.2.2 Evolutionary Relationships of 2.2.1 DNA . . . . . . . . . . . . . . . . . . . . . 39 Different Proteins . . . . . . . . . . . . 91 2.2.2 RNA . . . . . . . . . . . . . . . . . . . . . 41 4.2.3 Evolution by Differential Post- 2.3 Conclusion . . . . . . . . . . . . . . . . . . . . 44 transcriptional and Post- translationalProcessing:theOpioids 3 Information Processing in Cells. . . . . . . . 47 and Other Neuroactive Peptides . . 92 3.1 The Genetic Code . . . . . . . . . . . . . . . 48 4.3 Conclusion . . . . . . . . . . . . . . . . . . . . 95 3.2 Replication. . . . . . . . . . . . . . . . . . . . 49 3.3 ‘DNA Makes RNA and RNA Makes Protein’ . . . . . . . . . . . . . . . . . . . . . . 49 5 Manipulating Biomolecules . . . . . . . . . . . 96 3.3.1 Transcription. . . . . . . . . . . . . . . . 49 5.1 Restriction Endonucleases . . . . . . . . . 97 3.3.2 Post-transcriptional Processing . . . 56 5.2 Separation of Restriction Fragments. . 98 3.3.3 Translation . . . . . . . . . . . . . . . . . 60 5.3 Restriction Maps. . . . . . . . . . . . . . . . 98 BOX 3.1: Antisense and triplex 5.4 Recombination . . . . . . . . . . . . . . . . . 100 oligonucleotides. . . . . . . . . . . . . . 63 5.5 Cloning. . . . . . . . . . . . . . . . . . . . . . . 101 vi CONTENTS 5.5.1 Plasmids. . . . . . . . . . . . . . . . . . . 101 7.4 Proteins . . . . . . . . . . . . . . . . . . . . . . 148 5.5.2 Phage. . . . . . . . . . . . . . . . . . . . . 102 7.5 Mobility of Membrane Proteins . . . . . 150 5.5.3 Cosmids . . . . . . . . . . . . . . . . . . . 103 7.6 Synthesis of Biomembranes . . . . . . . . 151 5.5.4 Bacterial Artificial Chromosomes 7.7 Myelin and Myelination. . . . . . . . . . . 152 (BACs). . . . . . . . . . . . . . . . . . . . 103 7.8 The Submembranous Cytoskeleton . . . 155 5.5.5 Yeast Artifical Chromosomes 7.9 Junctions Between Cells. . . . . . . . . . . 158 (YACs). . . . . . . . . . . . . . . . . . . . 107 7.9.1 Tight Junctions . . . . . . . . . . . . . . 158 5.6 Isolating Bacteria Containing 7.9.2 Gap Junctions. . . . . . . . . . . . . . . 160 Recombinant Plasmids or Phage. . . . . 107 7.10 Gap Junctions and Neuropathology . 164 5.7 The ‘Shotgun’ Construction of 7.10.1 Deafness . . . . . . . . . . . . . . . . . . 164 ‘Genomic’ Gene Libraries. . . . . . . . . . 107 7.10.2 Cataract . . . . . . . . . . . . . . . . . . 164 5.8 A Technique for Finding a Gene in the 7.10.3 Charcot–Marie–Tooth (Type 2) Library. . . . . . . . . . . . . . . . . . . . . . . 108 Disease . . . . . . . . . . . . . . . . . . . 164 5.9 Construction of a ‘cDNA’ Gene 7.10.4 Spreading Hyperexcitability Library. . . . . . . . . . . . . . . . . . . . . . . 109 (Epilepsy) and Hypoexcitability 5.10 Fishing for Genes in a cDNA Library 111 (Spreading Depression). . . . . . . . 165 5.11 Positional Cloning . . . . . . . . . . . . . . 112 7.11 Conclusion and Forward Look. . . . . 165 5.12 The Polymerase Chain Reaction (PCR). . . . . . . . . . . . . . . . . . . . . . . 112 5.13 Sequence Analysis of DNA. . . . . . . . 115 5.14 Prokaryotic Expression Vectors for Eukaryotic DNA. . . . . . . . . . . . . . . 117 8 G-protein-coupled Receptors . . . . . . . . . . 167 5.15 Xenopus Oocyte as an Expression 8.1 Messengers and Receptors . . . . . . . . . 167 Vector for Membrane Proteins . . . . . 117 8.2 The 7TM Serpentine Receptors. . . . . . 169 5.16 Site-directed Mutagenesis . . . . . . . . . 119 8.3 G-proteins. . . . . . . . . . . . . . . . . . . . . 170 5.17 Gene Targeting and Knockout BOX 8.1: The GTPase superfamily. 171 Genetics . . . . . . . . . . . . . . . . . . . . . 121 8.4 G-protein Collision-coupling Systems . 172 5.18 Targeted Gene Expression . . . . . . . . 126 8.5 Effectors and Second Messengers . . . . 174 5.19 Hybridisation Histochemistry . . . . . . 126 8.5.1. Adenylyl Cyclases. . . . . . . . . . . . 174 5.20 DNA Chips. . . . . . . . . . . . . . . . . . . 127 8.5.2 PIP -phospholipase 2 5.21 Conclusion . . . . . . . . . . . . . . . . . . . 128 (Phospholipase C-bÞ. . . . . . . . . . . 176 8.6 Synaptic Significance of ‘Collision- 6 Genomics . . . . . . . . . . . . . . . . . . . . . . . 130 coupling’ Systems . . . . . . . . . . . . . . . 179 6.1 Some History . . . . . . . . . . . . . . . . . . 130 8.7 Networks of G-protein Signalling 6.2 Methodology. . . . . . . . . . . . . . . . . . . 131 Systems. . . . . . . . . . . . . . . . . . . . . . . 179 6.3SalientFeaturesoftheHumanGenome 132 8.8 The Adrenergic Receptor (AR). . . . . . 180 6.4 The Genes of Neuropathology . . . . . . 135 8.9 The Muscarinic Acetylcholine 6.5 Single Nucleotide Polymorphisms Receptor (mAChR) . . . . . . . . . . . . . . 183 (SNPs) . . . . . . . . . . . . . . . . . . . . . . . 136 8.10 Metabotropic Glutamate 6.6 Other Genomes. . . . . . . . . . . . . . . . . 137 Receptors (mGluRs). . . . . . . . . . . . . 187 6.7 Conclusion . . . . . . . . . . . . . . . . . . . . 138 8.11 Neurokinin Receptors (NKRs) . . . . . 188 8.12 Cannabinoid Receptors (CBRs). . . . . 189 7 Biomembranes. . . . . . . . . . . . . . . . . . . . 140 8.13 Rhodopsin. . . . . . . . . . . . . . . . . . . . 190 8.14 Cone Opsins . . . . . . . . . . . . . . . . . . 194 7.1 Lipids. . . . . . . . . . . . . . . . . . . . . . . . 140 8.15 Conclusion . . . . . . . . . . . . . . . . . . . 196 7.1.1 Phospholipids . . . . . . . . . . . . . . . 141 7.1.2 Glycolipids . . . . . . . . . . . . . . . . . 144 7.1.3 Cholesterol . . . . . . . . . . . . . . . . . 145 9 Pumps . . . . . . . . . . . . . . . . . . . . . . . . . 197 7.2 Membrane Order and Fluidity . . . . . . 147 9.1 Energetics. . . . . . . . . . . . . . . . . . . . . 197 7.3 Membrane Asymmetry. . . . . . . . . . . . 148 9.2 The Na++K+Pump . . . . . . . . . . . . . 200 CONTENTS vii 9.3 The Calcium Pump . . . . . . . . . . . . . . 201 11.6 Voltage-Sensitive Chloride Channels . . 268 BOX 9.1: Calmodulin . . . . . . . . . . 204 11.6.1 ClC Channels . . . . . . . . . . . . . . 268 9.4 Other Pumps and Transport 11.6.2 Cln Channels. . . . . . . . . . . . . . . 270 Mechanisms . . . . . . . . . . . . . . . . . . . 205 11.6.3 Phospholemman. . . . . . . . . . . . . 270 9.5 Conclusion . . . . . . . . . . . . . . . . . . . . 206 11.7 Channelopathies . . . . . . . . . . . . . . . 271 11.7.1 Potassium Channels . . . . . . . . . . 271 10 Ligand-gated Ion Channels . . . . . . . . . . 207 11.7.2 Calcium Channels . . . . . . . . . . . 271 11.7.3 Sodium Channels. . . . . . . . . . . . 271 10.1 The Nicotinic Acetylcholine Receptor 208 11.7.4 Chloride Channels . . . . . . . . . . . 272 10.1.1 Structure. . . . . . . . . . . . . . . . . . 208 11.8 Evolution of Ion Channels. . . . . . . . . 272 10.1.2 Function. . . . . . . . . . . . . . . . . . 213 11.9 Conclusion and Forward Look. . . . . . 274 10.1.3 Development. . . . . . . . . . . . . . . 219 10.1.4 Pathologies . . . . . . . . . . . . . . . . 221 12 Resting Potentials and Cable Conduction 277 10.1.5 CNS Acetylcholine Receptors . . . 222 12.1 Measurement of the Resting Potential 277 BOX 10.1: Evolution of the 12.2 The Origin of the Resting Potential. . 278 nAChRs . . . . . . . . . . . . . . . . . . . 222 12.3 Electrotonic Potentials and Cable 10.2 The GABA Receptor . . . . . . . . . . . 224 A Conduction. . . . . . . . . . . . . . . . . . . 281 10.2.1 Pathology . . . . . . . . . . . . . . . . . 225 12.3.1 Length . . . . . . . . . . . . . . . . . . . 283 10.3 The Glycine Receptor. . . . . . . . . . . . 226 12.3.2 Diameter. . . . . . . . . . . . . . . . . . 284 10.4 Ionotropic Glutamate Receptors 12.4 Conclusion . . . . . . . . . . . . . . . . . . . 285 (iGluRs) . . . . . . . . . . . . . . . . . . . . . 228 10.4.1 AMPA Receptors. . . . . . . . . . . . 229 13 Sensory Transduction . . . . . . . . . . . . . . 286 10.4.2 KA Receptors . . . . . . . . . . . . . . 229 13.1 Chemoreceptors. . . . . . . . . . . . . . . . 287 10.4.3 NMDA Receptors . . . . . . . . . . . 230 13.1.1 Chemosensitivity in BOX 10.2: The inositol Prokaryocytes . . . . . . . . . . . . . . 287 triphosphate (IP or InsP ) 3 3 13.1.2 Chemosensitivity in Vertebrates. . 292 receptor . . . . . . . . . . . . . . . . . . . 231 13.2 Photoreceptors. . . . . . . . . . . . . . . . . 297 10.5 Purinoceptors . . . . . . . . . . . . . . . . . 234 BOX 13.1: Retinitis pigmentosa. . . 300 10.6 Conclusion . . . . . . . . . . . . . . . . . . . 235 13.3 Mechanoreceptors . . . . . . . . . . . . . . 304 13.3.1 A Prokaryote Mechanoreceptor. . 305 11 Voltage-gated Channels. . . . . . . . . . . . . 237 13.3.2 Mechanosensitivity in 11.1 The KcsA Channel. . . . . . . . . . . . . . 238 Caenorhabditis elegans . . . . . . . . 309 11.2 Neuronal K+ Channels . . . . . . . . . . 241 13.3.3 Mechanosensitivity in 11.2.1 2TM(1P) Channels; Kir Channels 243 Vertebrates: Hair Cells . . . . . . . . 312 11.2.2 4TM(2P) Channels; K+ Leak 13.4 Conclusion . . . . . . . . . . . . . . . . . . . 318 Channels. . . . . . . . . . . . . . . . . . 245 11.2.3 6TM(1P) Channels; K Channels. 245 14 The Action Potential. . . . . . . . . . . . . . . 319 v BOX 11.1: Cyclic nucleotide-gated 14.1 Voltage-clamp Analyses . . . . . . . . . . 319 (CNG) channels. . . . . . . . . . . . . . 246 14.2 Patch-clamp Analyses. . . . . . . . . . . . 323 11.3 Ca2+ Channels . . . . . . . . . . . . . . . . 253 14.3 Propagation of the Action Potential . 325 11.3.1 Structure. . . . . . . . . . . . . . . . . . 255 BOX 14.1: Early history of the 11.3.2 Diversity. . . . . . . . . . . . . . . . . . 258 impulse. . . . . . . . . . . . . . . . . . . . 326 11.3.3 Biophysics. . . . . . . . . . . . . . . . . 258 14.4 Initiation of the Impulse. . . . . . . . . . 329 11.4 Na+ Channels. . . . . . . . . . . . . . . . . 259 BOX 14.2: Switching off neurons by 11.4.1 Structure. . . . . . . . . . . . . . . . . . 259 manipulating K+ channels . . . . . . 330 11.4.2 Diversity. . . . . . . . . . . . . . . . . . 262 14.5 Rate of Propagation. . . . . . . . . . . . . 331 11.4.3 Biophysics. . . . . . . . . . . . . . . . . 264 14.6 Conclusion . . . . . . . . . . . . . . . . . . . 333 11.5 Ion Selectivity and Voltage Sensitivity 267 11.5.1 Ion Selectivity . . . . . . . . . . . . . . 267 15 The Neuron as a Secretory Cell. . . . . . . 334 11.5.2 Voltage Sensitivity . . . . . . . . . . . 267 15.1 Neurons and Secretions . . . . . . . . . . 335 viii CONTENTS 15.2 Synthesis in the Perikaryon. . . . . . . . 336 16.6 Cannabinoids . . . . . . . . . . . . . . . . . 390 15.2.1 Co-translational Insertion. . . . . . 337 BOX 16.3: Reuptake neuro- 15.2.2 The Golgi Body and transmitter transporters . . . . . . . . 392 Post-translational Modification . . 339 16.7 Peptides . . . . . . . . . . . . . . . . . . . . . 393 15.3 Transport Along the Axon . . . . . . . . 342 16.7.1 Substance P. . . . . . . . . . . . . . . . 395 15.3.1 Microfilaments. . . . . . . . . . . . . . 344 16.7.2 Enkephalins. . . . . . . . . . . . . . . . 396 15.3.2 Intermediate Filaments (IFs). . . . 344 16.8 Cohabitation of Peptides and BOX 15.1: Subcellular geography of Non-peptides. . . . . . . . . . . . . . . . . . 397 protein biosynthesis in neurons. . . 345 16.9 Nitric Oxide (NO) . . . . . . . . . . . . . . 399 15.3.3 Microtubules (MTs). . . . . . . . . . 345 16.10 Conclusion. . . . . . . . . . . . . . . . . . . 400 15.3.4 The Axonal Cytoskeleton . . . . . . 346 15.3.5 Axoplasmic Transport 17 The Postsynaptic Cell. . . . . . . . . . . . . . 401 Summarised. . . . . . . . . . . . . . . . 353 17.1 Synaptosomes . . . . . . . . . . . . . . . . . 401 15.4 Exocytosis and Endocytosis at the 17.2 The Postsynaptic Density . . . . . . . . . 403 Synaptic Terminal . . . . . . . . . . . . . . 353 17.3 Electrophysiology of the Postsynaptic 15.4.1 Vesicle Mustering. . . . . . . . . . . . 354 Membrane. . . . . . . . . . . . . . . . . . . . 404 15.4.2 The Ca2+ Trigger. . . . . . . . . . . . 357 17.3.1 The Excitatory Synapse . . . . . . . 404 15.4.3 Vesicle Docking. . . . . . . . . . . . . 357 BOX 17.1: Cajal, Sherrington and 15.4.4 Transmitter Release . . . . . . . . . . 360 the beginnings of synaptology. . . . 406 15.4.5 Dissociation of Fusion Complex 17.3.2 The Inhibitory Synapse. . . . . . . . 408 and Retrieval and Reconstitution 17.3.3 Interaction of EPSPs and IPSPs . 410 of Vesicle Membrane . . . . . . . . . 361 17.4 Ion Channels in the Postsynaptic 15.4.6 Refilling of Vesicle. . . . . . . . . . . 362 Membrane. . . . . . . . . . . . . . . . . . . . 410 BOX 15.2: Vesicular neuro- 17.5 Second Messenger Control of Ion transmitter transporters . . . . . . . . 363 Channels. . . . . . . . . . . . . . . . . . . . . 412 15.4.7 Termination of Transmitter 17.6 Second Messenger Control of Gene Release . . . . . . . . . . . . . . . . . . . 364 Expression. . . . . . . . . . . . . . . . . . . . 415 15.4.8 Modulation of Release. . . . . . . . 365 17.7 The Pinealocyte. . . . . . . . . . . . . . . . 416 15.5 Conclusion . . . . . . . . . . . . . . . . . . . 365 17.8 Conclusion and Forward Look. . . . . 418 16 Neurotransmitters and Neuromodulators. 366 18 Developmental Genetics of the Brain. . . . 419 16.1 Acetylcholine. . . . . . . . . . . . . . . . . . 368 18.1 Introduction: ‘Ontology Recapitulates BOX 16.1: Criteria for Phylogeny’ . . . . . . . . . . . . . . . . . . . 419 neurotransmitters. . . . . . . . . . . . . 368 18.2 Establishing an Anteroposterior 16.2 Amino Acids. . . . . . . . . . . . . . . . . . 372 (A-P) Axis in Drosophila. . . . . . . . . . 421 16.2.1 Excitatory Amino Acids (EAAs): 18.3 Initial Subdivision of the Drosophila Glutamic Acid and Aspartic Embryo . . . . . . . . . . . . . . . . . . . . . 422 Acid . . . . . . . . . . . . . . . . . . . . . 372 18.4 The A-P Axis in Vertebrate Central 16.2.2 Inhibitory Amino Acids (IAAs): Nervous Systems. . . . . . . . . . . . . . . 423 g-Aminobutyric Acid and Glycine 374 18.5 Segmentation Genes in Mus musculus 425 BOX 16.2: Otto Loewi and 18.6 Homeosis and Homeotic Mutations . 425 vagusstoff . . . . . . . . . . . . . . . . . . 376 18.7 Homeobox Genes . . . . . . . . . . . . . . 426 16.3 Serotonin (¼5-Hydroxytryptamine, 18.8 Homeobox Genes and the Early 5-HT). . . . . . . . . . . . . . . . . . . . . . . 380 Development of the Brain. . . . . . . . . 427 16.4 Catecholamines . . . . . . . . . . . . . . . . 382 18.9 POU Genes and Neuronal 16.4.1 Dopamine (DA). . . . . . . . . . . . . 383 Differentiation. . . . . . . . . . . . . . . . . 431 16.4.2 Noradrenaline 18.10 Sequential Expression Of (¼Norepinephrine, NE) . . . . . . . 385 Transcription Factors in 16.5 Purines . . . . . . . . . . . . . . . . . . . . . . 389 Drosophila CNS. . . . . . . . . . . . . . . 433 CONTENTS ix 18.11 Pax-6: Developmental Genetics of 20.5.4 The CRE Site Again. . . . . . . . . . 502 Eyes and Olfactory Systems . . . . . . 434 20.5.5 Mossy Fibre Pathway. . . . . . . . . 503 18.12 Other Genes Involved in Neuronal 20.5.6 Histology . . . . . . . . . . . . . . . . . 503 Differentiation . . . . . . . . . . . . . . . . 436 20.5.7 Non-genomic Mechanisms . . . . . 503 18.13 Conclusion. . . . . . . . . . . . . . . . . . . 436 BOX 20.1: Dendritic spines . . . . . . 504 20.6 Conclusion . . . . . . . . . . . . . . . . . . . 506 19 Epigenetics of the Brain . . . . . . . . . . . . 437 21 Some Pathologies. . . . . . . . . . . . . . . . . 507 19.1 The Origins of Neurons and Glia . . . 438 21.1 Neuroses, Psychoses and the 19.2 Neural Stem Cells . . . . . . . . . . . . . . 443 Mind/Brain Dichotomy . . . . . . . . . . 508 19.3 Tracing Neuronal Lineages. . . . . . . . 445 21.2 Prions and Prion Diseases. . . . . . . . . 508 19.3.1 Retrovirus Tagging. . . . . . . . . . . 446 19.3.2 Enhancer Trapping. . . . . . . . . . . 446 21.3 Phenylketonuria (PKU) . . . . . . . . . . 511 19.4 Morphogenesis of Neurons. . . . . . . . 446 21.4 Fragile X Syndrome (FraX) . . . . . . . 513 19.5 Morphogenesis of the Drosophila 21.5 Neurofibromatoses. . . . . . . . . . . . . . 514 21.6 Motor Neuron Disease (MND). . . . . 514 Compound Eye . . . . . . . . . . . . . . . . 450 21.7 Huntington’s Disease (¼Chorea) 19.6 Growth Cones. . . . . . . . . . . . . . . . . 452 (HD). . . . . . . . . . . . . . . . . . . . . . . . 516 19.7 Pathfinding . . . . . . . . . . . . . . . . . . . 454 21.8 Depression . . . . . . . . . . . . . . . . . . . 518 BOX 19.1: Eph receptors and 21.8.1 Endogenous Depression . . . . . . . 519 ephrins . . . . . . . . . . . . . . . . . . . . 456 21.8.2 Exogenous Depression . . . . . . . . 519 19.8 Cell Adhesion Molecules (CAMs) . . . 457 21.8.3 Neurochemistry of Depression. . . 520 19.9 Growth Factors and Differential 21.8.4 Stress and Depression. . . . . . . . . 521 Survival. . . . . . . . . . . . . . . . . . . . . . 462 BOX 19.2: Neurotransmitters as 21.9 Parkinson’s Disease (PD) . . . . . . . . . 522 growth factors. . . . . . . . . . . . . . . 464 BOX 21.1 a-Synuclein. . . . . . . . . . 526 19.10 Morphopoietic Fields . . . . . . . . . . . 466 21.10 Alzheimer’s Disease (AD). . . . . . . . 526 21.10.1 Diagnosis. . . . . . . . . . . . . . . . . 527 19.11 Functional Sculpting. . . . . . . . . . . . 469 21.10.2 Aetiology. . . . . . . . . . . . . . . . . 527 19.12 Conclusion. . . . . . . . . . . . . . . . . . . 476 21.10.3 Molecular Pathology. . . . . . . . . 527 21.10.4 Environmental Influences: 20 Memory . . . . . . . . . . . . . . . . . . . . . . . 477 Aluminium . . . . . . . . . . . . . . . 536 20.1 Some Definitions . . . . . . . . . . . . . . . 478 21.10.5 The BAPtist Proposal: an 20.1.1 Classical Conditioning . . . . . . . . 479 Amyloid Cascade Hypothesis. . . 538 20.1.2 Operant Conditioning. . . . . . . . . 479 21.10.6 Therapy. . . . . . . . . . . . . . . . . . 538 20.2 Short- and Long-term Memory. . . . . 480 21.11 Conclusion. . . . . . . . . . . . . . . . . . . 539 20.2.1 Relation Between STM and LTM. . . . . . . . . . . . . . . . . . . . . 481 Appendix 1 Molecules and Consciousness. . . . 541 20.3 Where is the Memory Trace Located? 481 Appendix 2 Units . . . . . . . . . . . . . . . . . . . . 545 20.4 Invertebrate Systems . . . . . . . . . . . . 485 20.4.1 Thermal Conditioning in Appendix 3 Data . . . . . . . . . . . . . . . . . . . . 546 C. elegans . . . . . . . . . . . . . . . . . 486 Appendix 4 Genes. . . . . . . . . . . . . . . . . . . . 548 20.4.2 Drosophila. . . . . . . . . . . . . . . . . 487 Appendix5PhysicalModelsofIonConduction 20.4.3 Aplysia and the Molecular and Gating. . . . . . . . . . . . . . . . . . . . . . . . . 550 Biology of Memory . . . . . . . . . . 492 20.5 The Memory Trace in Mammals. . . . 498 Acronyms and Abbreviations . . . . . . . . . . . . 551 20.5.1 Post-tetanic Potentiation and Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . 554 Long-term Potentiation. . . . . . . . 499 20.5.2 Fibre Pathways in the Bibliography. . . . . . . . . . . . . . . . . . . . . . . . 560 Hippocampus . . . . . . . . . . . . . . 500 Index of Neurological Disease . . . . . . . . . . . 588 20.5.3 Perforant and Schaffer Collateral Fibres . . . . . . . . . . . . 501 Index. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 590 PREFACE Another six years have passed since I wrote the more a picture of an ever-changing quilt of prefacetothesecondeditionandthesubjectmatter chemical activity, bound together via synapses of molecular neurobiology has continued its andgapjunctionsandsecondandthirdmessengers explosive development. President Clinton did well leading to subtle modifications of a host of to designate the 1990s ‘the decade of the brain’. channels, growth factors and neurochemistry. Once again I have found it necessary to rewrite There is ample scope for the multitudinous states large sections of the text to incorporate new ofconsciousnesswealllivethrough.Throughitall developments and to design over fifty new and runs the thread of evolution and the work of the revised illustrations. In particular, the publication genes. More than ever we recognise that we are in2001 ofthefirst draft ofthe humangenomeand bound into a seamless web of living matter. the genomes of a number of other organisms Solutions found to biological problems half a merited the insertion of a new chapter (chapter billion years ago in sea squirt, worm and fly are 6).Thegreatadvancesinunravellingthestructures stillatworkinustoday.Thisistrulyremarkable:a (at the atomic level) of some of the voltage-gated confirmation of Charles Darwin’s insight and a channels has also meant that chapter 11 has been revolution in our understanding of our place in completely redesigned. Otherwise the overall orga- Nature. nisation of the book remains unchanged. I have The huge value of the comparative approach is taken the opportunity to reproduce the intricately confirmedbythefindingthatwhenthegenomesof beautiful representations of some of the great DrosophilaandHomosapiensarecompared,177of molecules which lie at the root of molecular the289knownhumandiseasegenesarealsofound neurobiology. These are collected in a colour in the fly. The medical significance of molecular section and my thanks are due to the scientists neurobiology is stressed throughout the following who gave permission. Nowhere, it seems to me, is pages. Recent advances in our knowledge of the truth of Schelling’s dictum that ‘architecture is channel proteins gives insight into the causes of a frozen music’ more apparent than in these magni- number of troubling conditions and neural stem ficent structures. cell research gives hope to those suffering from Prefaces although placed at the beginning are damaged nervous systems and even to those facing generally (as is this) the last item to be written. the neurodegenerations of old age. Knowledge, as They provide an opportunity for a concluding ever, gives power. Our increasing ability to control overview. Having just read and corrected page and manipulate can, nevertheless, be used for ill as proofs an author has, transiently, the whole book well as good. At the outset of the twenty-first in his head. I have been impressed once again by centurywearejustbeginningtodeveloptechniques thesheercomplexityindepthofanimalandhuman for subtly altering the functioning of the brain. In brains. We no longer have the telephone exchange experimental animals it has become possible to image of the early twentieth century, but much switch genes controlling the activity of specific