elements of molecular neurobiology 3d ed - c. u. m. smith

Elements
of
Molecular
Neurobiology
Third Edition
Elements of Molecular Neurobiology. C. U. M. Smith
Copyright
 2002 John Wiley & Sons, Ltd.
ISBNs: 0-470-84353-5 (HB); 0-471-56038-3 (PB)
For Rosemary
Always in my heart
Elements
of
Molecular
Neurobiology
Third Edition
C. U. M. SMITH
Department of Vision Sciences
Aston University
Birmingham, UK
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CONTENTS
Preface xi
Preface to the First Edition . . xiii
Preface to the Second Edition xv
1 Introductory Orientation . . 1
1.1 Outline of Nervous Systems . 2
1.2 Vertebrate Nervous Systems . 4
1.3 Cells of the Nervous Systems 7
1.3.1 Neurons 7

1.3.2 Glia . . . 11
1.4 Organisation of Synapses . . . 14
1.5 Organisation of Neurons in the Brain . 16
2 The Conformation of Informational
Macromolecules 22
2.1 Proteins . . . 22
2.1.1 Primary Structure . 23
2.1.2 Secondary Structure 28
2.1.3 Tertiary Structure . 35
2.1.4 Quaternary Structure . . . 37
2.1.5 Molecular Chaperones . . 38
2.2 Nucleic Acids . . . 39
2.2.1 DNA . . 39
2.2.2 RNA . . 41
2.3 Conclusion . 44
3 Information Processing in Cells . 47
3.1 The Genetic Code 48
3.2 Replication . 49
3.3 ‘DNA Makes RNA and RNA Makes
Protein’ . . . 49
3.3.1 Transcription. 49
3.3.2 Post-transcriptional Processing . . . 56
3.3.3 Translation . . 60
B
OX 3.1: Antisense and triplex
oligonucleotides . . . 63
3.4 Control of the Expressi on of Genetic
Information . 65
3.4.1 Genomic Control. . . 66
3.4.2 Transcriptional Control . . . . . . . . 67

B
OX 3.2: Oncogenes, proto-
oncogenes and IEGs 69
3.4.3 Post-transcriptional Control . . . . . 73
3.4.4 Translational Control 74
3.4.5 Post-translational Control. . . . . . . 75
3.5 Conclusion . . 76
4 Molecular Evolution . . 77
4.1 Mutation . . . 79
4.1.1 Point Mutations . . . 79
4.1.2 Proof-reading and Repair
Mechanisms . . 80
4.1.3 Chromosomal Mutations . . . . . . . 84
4.2 Protein Evolution . 87
4.2.1 Evolutionary Development of
Protein Molecules and
Phylogenetic Relationships . . . . . . 87
4.2.2 Evolutionary Relationships of
Different Proteins . . 91
4.2.3 Evolution by Differential Post-
transcriptional and Post-
translational Processing: the Opioids
and Other Neuroactive Peptides . . 92
4.3 Conclusion . . 95
5 Manipulating Biomolecules 96
5.1 Restriction Endonucleases . . . . . . . . . 97
5.2 Separation of Restriction Fragments . . 98
5.3 Restriction Maps . . 98
5.4 Recombination . . . 100
5.5 Cloning. 101

5.5.1 Plasmids . 101
5.5.2 Phage . . . 102
5.5.3 Cosmids . 103
5.5.4 Bacterial Artificial Chromosomes
(BACs) . . 103
5.5.5 Yeast Artifical Chromosomes
(YACs) . . 107
5.6 Isolating Bacteria Containing
Recombinant Plasmids or Phage . . . . . 107
5.7 The ‘Shotgun’ Construction of
‘Genomic’ Gene Libraries 107
5.8 A Technique for Finding a Gene in the
Library . 108
5.9 Construction of a ‘cDNA’ Gene
Library . 109
5.10 Fishing for Genes in a cDNA Library 111
5.11 Positional Cloning 112
5.12 The Polymerase Chain Reaction
(PCR) . 112
5.13 Sequence Analysis of DNA. . 115
5.14 Prokaryotic Expression Vectors for
Eukaryotic DNA . 117
5.15 Xenopus Oocyte as an Expression
Vector for Membrane Proteins . . . . . 117
5.16 Site-directed Mutagenesis . . . 119
5.17 Gene Targeting and Knockout
Genetics . . . 121
5.18 Targeted Gene Expression . . 126
5.19 Hybridisation Histochemistry 126
5.20 DNA Chips. 127

5.21 Conclusion . 128
6 Genomics . 130
6.1 Some History 130
6.2 Methodology. 131
6.3 Salient Features of the Human Genome 132
6.4 The Genes of Neuropathology 135
6.5 Single Nucleotide Polymorphisms
(SNPs) . 136
6.6 Other Genomes . . . 137
6.7 Conclusion . . 138
7 Biomembranes 140
7.1 Lipids . . 140
7.1.1 Phospholipids . 141
7.1.2 Glycolipids . . . 144
7.1.3 Cholesterol . . . 145
7.2 Membrane Order and Fluidity 147
7.3 Membrane Asymmetry. . 148
7.4 Proteins . 148
7.5 Mobility of Membrane Proteins 150
7.6 Synthesis of Biomembranes . . . 151
7.7 Myelin and Myelination . . 152
7.8 The Submembranous Cytoskeleton . . . 155
7.9 Junctions Between Cells . . 158
7.9.1 Tight Junctions . 158
7.9.2 Gap Junctions . . 160
7.10 Gap Junctions an d Neuropathology . 164
7.10.1 Deafness . 164
7.10.2 Cataract . 164
7.10.3 Charcot–Marie–Tooth (Type 2)
Disease . . 164

7.10.4 Spreading Hyperexcitability
(Epilepsy) and Hypoexcitability
(Spreading Depression) . . . 165
7.11 Conclusion and Forward Look 165
8 G-protein-coupled Receptors . 167
8.1 Messengers and Receptors 167
8.2 The 7TM Serpentine Receptors. 169
8.3 G-proteins 170
B
OX 8.1: The GTPase superfamily. 171
8.4 G-protein Collision-coupling Systems . 172
8.5 Effectors and Second Messengers . . . . 174
8.5.1. Adenylyl Cyclases . . . 174
8.5.2 PIP
2
-phospholipase
(Phospholipase C-bÞ 176
8.6 Synaptic Significance of ‘Collision-
coupling’ Systems . . 179
8.7 Networks of G-protein Signalling
Systems. . 179
8.8 The Adrenergic Receptor (AR) . 180
8.9 The Muscarinic Acetylcholine
Receptor (mAChR) . 183
8.10 Metabotropic Glutamate
Receptors (mGluRs) 187
8.11 Neurokinin Receptors (NKRs) 188
8.12 Cannabinoid Receptors (CBRs) 189
8.13 Rhodopsin. . . 190
8.14 Cone Opsins . 194

8.15 Conclusion . . 196
9 Pumps 197
9.1 Energetics 197
9.2 The Na
+
+K
+
Pump 200
vi
CONTENTS
CONTENTS vii
9.3 The Calcium Pump . . . 201
B
OX 9.1: Cal modulin . . . 204
9.4 Other Pumps and Transport
Mechanisms 205
9.5 Conclusion . 206
10 Ligand-gated Ion Channels . . . 207
10.1 The Nicotinic Acetylcholine Receptor 208
10.1.1 Structure . . . 208
10.1.2 Function . . . 213
10.1.3 Development 219
10.1.4 Pathologies . 221
10.1.5 CNS Acetylcholine Receptors . . . 222
B
OX 10.1: Evolution of the
nAChRs 222
10.2 The GABA
A
Receptor 224

10.2.1 Pathology . . 225
10.3 The Glycine Receptor. 226
10.4 Ionotropic Glutamate Receptors
(iGluRs) . . 228
10.4.1 AMPA Receptors. 229
10.4.2 KA Receptors . . . 229
10.4.3 NMDA Receptors 230
B
OX 10.2: The inositol
triphosphate (IP
3
or InsP
3
)
receptor 231
10.5 Purinoceptors . . 234
10.6 Conclusion 235
11 Voltage-gated Channels. . 237
11.1 The KcsA Channel. . . 238
11.2 Neuronal K
+
Channels . . . 241
11.2.1 2TM(1P) Channels; Kir Channels 243
11.2.2 4TM(2P) Channels; K
+
Leak
Channels . . . 245
11.2.3 6TM(1P) Channels; K
v
Channels. 245

B
OX 11.1: Cyclic nucleotide-gated
(CNG) channels. . . 246
11.3 Ca
2+
Channels . 253
11.3.1 Structure . . . 255
11.3.2 Diversity . . . 258
11.3.3 Biophysics . . 258
11.4 Na
+
Channels . . 259
11.4.1 Structure . . . 259
11.4.2 Diversity . . . 262
11.4.3 Biophysics . . 264
11.5 Ion Selectivity and Voltage Sensitivity 267
11.5.1 Ion Selectivity . . . 267
11.5.2 Voltage Sensitivity 267
11.6 Voltage-Sensitive Chloride Channels . . 268
11.6.1 ClC Channels 268
11.6.2 Cln Channels . 270
11.6.3 Phospholemman. . . 270
11.7 Channelopathies . 271
11.7.1 Potassium Channels 271
11.7.2 Calcium Channels . 271
11.7.3 Sodium Channels . . 271
11.7.4 Chloride Channels . 272
11.8 Evolution of Ion Channels . . . . . . . . . 272
11.9 Conclusion and Forward Look . . . . . . 274
12 Resting Potentials and Cable Conduction 277

12.1 Measurement of the Resting Potential 277
12.2 The Origin of the Resting Potential . . 278
12.3 Electrotonic Potentials and Cable
Conduction . 281
12.3.1 Length . 283
12.3.2 Diameter 284
12.4 Conclusion . 285
13 Sensory Transduction 286
13.1 Chemoreceptors . . 287
13.1.1 Chemosensitivity in
Prokaryocytes 287
13.1.2 Chemosensitivity in Vertebrates . . 292
13.2 Photoreceptors. . . 297
B
OX 13.1: Ret initis pigmentosa . . . 300
13.3 Mechanoreceptors 304
13.3.1 A Prokaryote Mechanoreceptor. . 305
13.3.2 Mechanosensitivity in
Caenorhabditis elegans . . . . . . . . 309
13.3.3 Mechanosensitivity in
Vertebrates: Hair Cells . . . . . . . . 312
13.4 Conclusion . 318
14 The Action Potential. 319
14.1 Voltage-clamp Analyses 319
14.2 Patch-clamp Analyses. . 323
14.3 Propagation of the Action Potential . 325
B
OX 14.1: Ear ly history of the
impulse . . 326
14.4 Initiation of the Impulse 329

B
OX 14.2: Switching off neurons by
manipulating K
+
channels . . . . . . 330
14.5 Rate of Propagation. . . 331
14.6 Conclusion . 333
15 The Neuron as a Secretory Cell . . . . . . . 334
15.1 Neurons and Secretions 335
viii CONTENTS
15.2 Synthesis in the Perikaryon . . 336
15.2.1 Co-translational Insertion 337
15.2.2 The Golgi Body and
Post-translational Modification . . 339
15.3 Transport Along the Axon . . 342
15.3.1 Microfilaments 344
15.3.2 Intermediate Filaments (IFs) . . . . 344
B
OX 15.1: Subcellular geography of
protein biosynthesis in neurons . . . 345
15.3.3 Microtubules (MTs) 345
15.3.4 The Axonal Cytoskeleton 346
15.3.5 Axoplasmic Transport
Summarised . . 353
15.4 Exocytosis and Endocytosis at the
Synaptic Terminal 353
15.4.1 Vesicle Mustering. . 354
15.4.2 The Ca
2+
Trigger. . 357

15.4.3 Vesicle Docking . . . 357
15.4.4 Transmitter Release 360
15.4.5 Dissociation of Fusion Complex
and Retrieval and Reconstitution
of Vesicle Membrane . . . 361
15.4.6 Refilling of Vesicle . 362
B
OX 15.2: Vesicular neuro-
transmitter transporters . . 363
15.4.7 Termination of Transmitter
Release . 364
15.4.8 Modulation of Release . . 365
15.5 Conclusion . 365
16 Neurotransmitters and Neuromodulators . 366
16.1 Acetylcholine 368
B
OX 16.1: Criteria for
neurotransmitters. . . 368
16.2 Amino Acids 372
16.2.1 Excitatory Amino Acids (EAAs):
Glutamic Acid and Aspartic
Acid . . . 372
16.2.2 Inhibitory Amino Acids (IAAs):
g-Aminobutyric Acid and Glycine 374
B
OX 16.2: Otto Loewi and
vagusstoff 376
16.3 Serotonin (¼5-Hydroxytryptamine,
5-HT) . 380
16.4 Catecholamines . . 382

16.4.1 Dopamine (DA). . . 383
16.4.2 Noradrenaline
(¼Norepinephrine, NE) . 385
16.5 Purines 389
16.6 Cannabinoids 390
B
OX 16.3: Reuptake neuro-
transmitter transporters . . . 392
16.7 Peptides 393
16.7.1 Substance P . . . 395
16.7.2 Enkephalins. . . 396
16.8 Cohabitation of Peptides and
Non-peptides . 397
16.9 Nitric Oxide (NO) . 399
16.10 Conclusion. . 400
17 The Postsynaptic Cell . 401
17.1 Synaptosomes 401
17.2 The Postsynaptic Density 403
17.3 Electrophysiology of the Postsynaptic
Membrane. . . 404
17.3.1 The Excitatory Synapse . . 404
B
OX 17.1: Cajal, Sherrington and
the beginnings of synaptology . . . . 406
17.3.2 The Inhibitory Synapse. . . 408
17.3.3 Interaction of EPSPs and IPSPs . 410
17.4 Ion Channels in the Postsynaptic
Membrane. . . 410
17.5 Second Messenger Control of Ion
Channels 412

17.6 Second Messenger Control of Gene
Expression. . . 415
17.7 The Pinealocyte . . . 416
17.8 Conclusion and Forward Look 418
18 Developmental Genetics of the Brain. . . . 419
18.1 Introduction: ‘Ontology Recapitulates
Phylogeny’ . . 419
18.2 Establishing an Anteroposterior
(A-P) Axis in Drosophila 421
18.3 Initial Subdivision of the Drosophila
Embryo 422
18.4 The A-P Axis in Vertebrate Central
Nervous Systems . . 423
18.5 Segmentation Genes in Mus musculus 425
18.6 Homeosis and Homeotic Mutations . 425
18.7 Homeobox Genes . 426
18.8 Homeobox Genes and the Early
Development of the Brain 427
18.9 POU Genes and Neuronal
Differentiation 431
18.10 Sequential Expression Of
Transcription Factors in
Drosophila CNS 433
18.11 Pax-6: Developmental Genetics of
Eyes and Olfactory Systems . . . . . . 434
18.12 Other Genes Involved in Neuronal
Differentiation . 436
18.13 Conclusion 436
19 Epigenetics of the Brain . 437
19.1 The Origins of Neurons and Glia . . . 438

19.2 Neural Stem Cells . . . 443
19.3 Tracing Neuronal Lineages . 445
19.3.1 Retrovirus Tagging 446
19.3.2 Enhancer Trapping 446
19.4 Morphogenesis of Neurons . 446
19.5 Morphogenesis of the Drosophila
Compound Eye . 450
19.6 Growth Cones . . 452
19.7 Pathfinding 454
B
OX 19.1: Eph receptors and
ephrins . 456
19.8 Cell Adhesion Molecules (CAMs) . . . 457
19.9 Growth Factors and Differential
Survival. . . 462
B
OX 19.2: Neurotransmitters as
growth factors 464
19.10 Morphopoietic Fields 466
19.11 Functional Sculpting. 469
19.12 Conclusion 476
20 Memory 477
20.1 Some Definitions 478
20.1.1 Classical Conditioning . 479
20.1.2 Operant Conditioning. . 479
20.2 Short- and Long-term Memory . . . . . 480
20.2.1 Relation Between STM and
LTM 481
20.3 Where is the Memory Trace Located? 481
20.4 Invertebrate Systems . 485

20.4.1 Thermal Conditioning in
C. elegans 486
20.4.2 Drosophila 487
20.4.3 Aplysia and the Molecular
Biology of Memory . . . 492
20.5 The Memory Trace in Mammals . . . . 498
20.5.1 Post-tetanic Potentiation and
Long-term Potentiation. 499
20.5.2 Fibre Pathways in the
Hippocampus . . . 500
20.5.3 Perforant and Schaffer
Collateral Fibres . 501
20.5.4 The CRE Site Again 502
20.5.5 Mossy Fibre Pathway. . . . . . . . . 503
20.5.6 Histology . . . 503
20.5.7 Non-genomic Mechanisms . . . . . 503
B
OX 20.1: Dendritic spines . . . . . . 504
20.6 Conclusion . 506
21 Some Pathologies 507
21.1 Neuroses, Psychoses and the
Mind/Brain Dichotomy 508
21.2 Prions and Prion Diseases. . . . . . . . . 508
21.3 Phenylketonuria (PKU) 511
21.4 Fragile X Synd rome (FraX) . . . . . . . 513
21.5 Neurofibromatoses 514
21.6 Motor Neuron Disease (MND) . . . . . 514
21.7 Huntington’s Disease (¼Chorea)
(HD) 516
21.8 Depression . 518

21.8.1 Endogenous Depression . . . . . . . 519
21.8.2 Exogenous Depression . . . . . . . . 519
21.8.3 Neurochemistry of Depression. . . 520
21.8.4 Stress and Depression. . . . . . . . . 521
21.9 Parkinson’s Disease (PD) . . . . . . . . . 522
B
OX 21.1 a-Synuclein 526
21.10 Alzheimer’s Disease (AD) . . . . . . . . 526
21.10.1 Diagnosis. . . 527
21.10.2 Aetiology. . . 527
21.10.3 Molecular Pathology. . . . . . . . . 527
21.10.4 Environmental Influences:
Aluminium . 536
21.10.5 The BAPtist Proposal: an
Amyloid Cascade Hypothesis. . . 538
21.10.6 Therapy 538
21.11 Conclusion. 539
Appendix 1 Molecules and Consciou sness 541
Appendix 2 Units 545
Appendix 3 Data 546
Appendix 4 Genes 548
Appendix 5 Physical Models of Ion Conduction
and Gating 550
Acronyms and Abbreviations 551
Glossary 554
Bibliography 560
Index of Neurological Disease 588
Index 590
CONTENTS ix
PREFACE

Another six years have passed since I wrote the
preface to the second edition and the subject matter
of molecular neurobiology has continued its
explosive development. President Clinton did well
to designate the 1990s ‘the decade of the brain’.
Once again I have found it necessary to rewrite
large sections of the text to incorporate new
developments and to design over fifty new and
revised illustrations. In particular , the publication
in 2001 of the first draft of the human genome and
the genomes of a number of other organisms
merited the insertion of a new chapter (chapter
6). The great advances in unravelling the structures
(at the atomic level) of some of the voltage-gated
channels has also meant that chapter 11 has been
completely redesigned. Otherwise the overall orga-
nisation of the book remains unchanged. I have
taken the opportunity to reproduce the intricately
beautiful representations of some of the great
molecules which lie at the root of molecular
neurobiology. These are collected in a colour
section and my thanks are due to the scientists
who gave permission. Nowhere, it seems to me, is
the truth of Schelling’s dictum that ‘architecture is
frozen music’ more apparent than in these magni-
ficent structures.
Prefaces although placed at the beginning are
generally (as is this) the last item to be written.
They provide an opportunity for a concluding
overview. Having just read and corrected page

proofs an author has, transiently, the whole book
in his head. I have been impressed once again by
the sheer complexity in depth of animal and human
brains. We no longer have the telephone exchange
image of the early twentieth century, but much
more a picture of an ever-changing quilt of
chemical activity, bound together via synapses
and gap junctions and second and third messengers
leading to subtle modifications of a host of
channels, growth factors and neurochemistry.
There is ample scope for the multitudinous states
of consciousness we all live through. Through it all
runs the thread of evolution and the work of the
genes. More than ever we recognise that we are
bound into a seamless web of living matt er.
Solutions found to biological problems half a
billion years ago in sea squirt, worm and fly are
still at work in us today. This is truly remarkable: a
confirmation of Charles Darwin’s insight and a
revolution in our understanding of our place in
Nature.
The huge value of the comparative approach is
confirmed by the finding that when the genomes of
Drosophila and Homo sapiens are compared, 177 of
the 289 known human disease genes are also found
in the fly. The medical significance of molecular
neurobiology is stressed throughout the following
pages. Recent advances in our knowledge of
channel proteins gives insight into the causes of a
number of troubling conditions and neural stem

cell research gives hope to those suffering from
damaged nervous systems and even to those facing
the neurodegenerations of old age. Knowledge, as
ever, gives power. Our increasing ability to control
and manipulate can, nevertheless, be used for ill as
well as good. At the outset of the twenty-first
century we are just beginning to develop techniques
for subtly altering the functioning of the brain. In
experimental animals it has become possible to
switch genes controlling the activity of specific
groups of nerve cells on and off. We begin to see
how, in the years to come, we may gain presently
unthinkable ability to control the operation of the
brain. The ethical issues involved are already
beginning to trouble forward thinkers.
Neurobiology, especially molec ular neurobiology,
is becoming too important just to be left to the
experts.
Even more than in previous editions this one can
only be an introduction. It is impossible to place
within the confines of a manageable book all the
details of the burgeoning subject . I have been only
too well aware of how much I have left out and of
how many alternative assessments have had to be
passed over. I have accordingly developed the
bibliographies by including not only printed
sources but also relevant web sites. I hope that
students will be sufficiently intrigued with what
they find in the following pages to follow up their
interest through these references.

Finally, as in previous editions, I have many
debts to acknowledge. Once more I have to thank
the many scientists who have given their permission
to reproduce their illustrations. Once again I have
to thank my publishers and their illustrators and
proof-readers for turning a complex typescript into
a presentable text. But, finally, I have to say once
more that the final responsibility for the accuracy
or otherwise of the following pages remains with its
author.
CUMS
July 2002
xii
PREFACE
PREFACE TO THE FIRST EDITION
This book is intentionally entitled ‘elements’. It is
intended as an introductory account of what is now
a vast and rapidly expanding subject. Indeed so
rapid is the advance that any writer finds difficulty
in steering betw een the Scylla of up-to-dateness
(with its danger of rebuttal) and the Charybdis of
received understanding (with its danger of obsoles-
cence). I hardly expect to have safely navigated
between these twin sirens at first attempt. But I
hope to have avoided shipwreck to the extent that
further attempts can be made in subsequent
editions. To this end I would welcome critical
(I hope constr uctively critical) comments so that
the text can be updated and improved in the years
ahead.

The elements upon which I have based my
account have been relevant parts of molecular
biology, biophysics and neurobiology. Several
themes have wound their way through the book
as if they were leitmotivs. Any biologist must see
his subject from an evolutionary perspective and
this theme is never far from the surface. Any
biophysicist must recognise that the operation of
nervous systems depends on the flows of ions
across membranes; this theme, also, recurs
throughout the text. Any molecular biologist must
approach the subject in terms of the structure and
function of great and complex molecules. From the
beginning to the end of the book the operation of
these intricately beautiful structures is a central
concern. They are shown to underly not only action
potentials and synaptic transmission but also,
multiplied up through the architecture of the brain,
to determine such holistic phenomena as memory
and psychopathology.
Because of the interdisciplinary nature of the
subject I have tried to make the book accessible to
as broad a readership as possible. It is for this
reason that I have started with an introductory
account of animal brains, in particular mammalian
brains, and it is for this reason that I have included
an extensive glossary and a list of the acronyms
with which the subject abounds. After the intro-
ductory chapter I have attempted to start at the
beginning, at the molecular level, and work

upwards through considerations of membrane,
ion fluxes, sensory transduction, nerve impulses
and synaptic biochemistry to end with such higher
level phenomena as neuroembryology, memory
and neuropathology. I have hoped to show that
the molecular approach is beginning to provide a
coherent theory of the brain’s structure and
functioning. At the same time I have hoped to
emphasise that the complexity of the ‘two handfuls
of por ridge’ within our skulls precludes any crass
and over-ha sty reductionism. Molecular ap-
proaches to the brain are, nevertheless, beginning
to give us considerable power: in order to use it well
our decisions must be informed with an unde r-
standing of the underlying scienc e.
Leonardo da Vinci annotated one of his anatomi-
cal drawings thus: ‘O Writer, with what words will
you describe with like perfection the entire config-
uration as the design here makes . . . and the longer
you write, minutely, the more you will confuse the
mind of the auditor . . .’ (trans. Keele). Accordingly I
make no apology for supplementing my text with
numerous illustrations. This, moreover, is the place
to repay a debt of gratitude to the illustrator at my
publishers who was able to transform my pencil
sketches into finished and stylistically consistent
figures. I hope that these, as Leonardo insisted, go
some way to clarifying the written descriptions.
Equally I owe an immense debt of gratitude to the
many scientists who kindly allowed me to reprint

their ha lf-tones and line drawings. These latter debts
are acknowledged in the figure legends.
Last, but far from least, I would like to acknow-
ledge the anonymous reviewers who read the first
drafts of many of my chapters. I have benefited
greatly from their comments though hardly dare to
hope that all my errors have thereby been eliminated.
This is also the place to thank the editorial staff at
John Wiley who provided indispensable help in
integrating a complicated typescript. I cannot finish,
however, without acknowledging the generations of
students who have listened to my lectures (without
too much complaint) and who by their conscious and
unconscious reactions have taught me what little I
know of developing a subject in a consistent and
coherent fashion. Nor can I finish without acknow-
ledging the help of my wife who, as with previous
books, has put up with absences of mind and
company and remained the most loyal of critics.
CUMS
February 1989
xiv
PREFACE TO THE FIRST EDITION
PREFACE TO THE SECOND EDITION
In the six years since I wrote my preface to the first
edition the subject matter of molecular neuro-
biology has undergone explosive development. In
attempting to incorporate the most important of
these new understandings I have found myself
rewriting large sections of the text and designing

well over a hundred new illustrations. In particular
the exciting progress in developmental neuro-
biology seemed to merit an entirely new chapter.
Nevertheless, in spite of the huge accession of
knowledge since the late 1980s I have (with the
exception of this new chapter) kept the overall
structure of the book unchanged. I have started
with the molecular biology of nucleic acids,
proteins and membranes and proceeded to those
all-important elements, the multitudinous
channels and receptors, with which neuronal (and
neuroglial) membranes are studded. Here the
developments since the 1980s have been astonish-
ing. Somewhere approaching a hundred of these
great molecular complexes have been isolated and
analysed, often in great detail. This fascinating
topic leads naturally to a consideration of mem-
brane biophysics and this, in turn, to an account of
the molecular biology of sensory cells and the
biophysics of nerve impulse propagation. An out-
line of the transmission of the impulse along a
nerve fibre leads naturally to a group of chapters on
the synapse, that most central of the brain’s
organelles. A final group of chapters then deals
with the development of the brain, its genetic
control, and the closely associated top ic of mem-
ory. The book ends, as before, with a consideration
of what can go wrong. Increasingly, today,
neuropathologies are being traced to the molecular
level. The hope strengthens that with ever greater

understanding of molecular neurobiology effective
therapies can be developed to ameliorate and/or
prevent these devastating conditions.
My approach to the subject matter of the book
remains the same as in the first edition. Molecular
neurobiology is not written in tablets of stone,
a fossilised unchanging body of facts. It is a living,
developing subject. I have, accordingly, sought to
show something of the excitement of the chase, of
how neurobiologists have isolated and analysed the
crucial molecular elements of the brain and how
they have used a wide spectrum of techniques to
investigate their function. Throughout the book,
too, I have retained the emphasis on the evolu-
tionary dimension. Indeed this dimension has
become yet more prominent in the years since the
first edition was printed and now forms a major
and recurring theme. I have also retained the stress
on the molecular causes of many neuropathologies,
not only in Chapter 20, but throughout the book.
Finally, I have sought to integrate our under-
standing of molecular neurobiology so that the
book does not present a mere sequence of disparate
chapters and sections but strives to provide a
coherent theory of the brain in health and disease.
I have also introduced a number of boxes to deal
with topics branching out from the main narrative
or with areas of historical and philosophical
interest. The bibliography has been expanded and
updated and if the book does nothing else I hope it

can provide an entry to the vast journal literature.
As in the first edition I have innumerable debts
to acknowledge. Once again I have to thank the
many scientists who have given me permission to
reproduce or adapt their illustrations and, of
course, more generally, for the uncountable hours
in the laboratory from which the data and
interpretations described in the following pages
have emerged. I have also to renew thanks to my
publishers and their illustrators who have once
again transform ed a complicated and many-sided
typescript into a unified text. Thanks are also due
to the anonymous referees who read and commen-
ted on an early version of the revision. I have
gained much from their advice and have wherever
possible incorporated their suggested improve-
ments. Much help has also been provided by
colleagues at Aston, both academic staff and
students. Professor Richard Leuchtag at Texas
Southern University has very kindly combed the
first edition for mistakes, typographical and other,
and I have greatly profited by his comments,
especially on the biophysical areas. But, as is
customarily said, the final responsibility for the
accuracy or otherwise of the text must ultimately
remain with its author. I cannot finish without
referring once again to my wife to whom this
second edition is dedicated.
CUMS
January 1996

xvi
PREFACE TO THE SECOND EDITION
COLOUR PLATES
Plate 1 Rhodopsin. (A) Ribbon diagrams orthogonal to plane of membrane (stereopair). Defocus eyes to get 3D
effect. (B) View from cytoplasmic (interdisc) side of membrane. (C) View from extracellular (intradisc) side of
membrane. The ribbons represent alpha-helices and are numbered I–VIII. Note that helix VIII does not traverse the
membrane but runs parallel to the cytoplasmic surface (see also B). Anti-parallel beta-strands on the extracellular
(intradisc) end of the molecule are labelled 1, 2, 3 and 4 and are shown as arrows (see also C). 11-cis retinene (not
shown) nestles in the centre of the seven TM helices and holds the whole structure in its inactive state. Note that the
molecule in (A) is the other way up from its representation in figure 8.25. Reprinted with permission from Pazewski,
K. et al., 2000, ‘Crystal structure of Rhodopsin: A G-Protein-Coupled Receptor’, Science, 289, 740. Copyright (2000)
American Association for the Advancement of Science.
Elements of Molecular Neurobiology. C. U. M. Smith
Copyr ight
 2002 John Wiley & Sons, L td.
ISBNs: 0-470-84353-5 (HB); 0-471-56038-3 (PB)
ELEMENTS OF MOLECULAR NEUROBIOLOGY
A
B
Plate 2 Ca
2+
pump. (A) Ribbon diagram. (B) Cylinder diagrams (alpha-helices represented by cylinders). The
transmembrane helices are numbered 1–10. The model is orientated so that the longest helix, M5, is vertical and
parallel to the plane of the paper. It is 60 A
˚
in length and hence provides a scale bar. The right hand diagram is
rotated 508 around M5. The three cytoplasmic domains are labelled A, N and P (see text pp. 203–5) and helices in A
and P are also numbered. Beta-strands are represented by arrows. D351 (Asp
351
) is the residue at which

phosphorylation occurs and TNP-AMP shows where the adenosine of ATP attaches to the nucleotide domain. PLN
and TG indicate the binding sites for phospholamban and thapsigargin and a purple sphere represents one of the
two Ca
2+
ions on its transmembrane binding site. For other detail consult reference cited below. Note, finally, that the
models are the other way up to the figures in chapter 9. Reprinted with permission from Toyoshima, C. et al., 2000,
‘Crystal structure of the calcium pump of sarcoplasmic reticulum at 2.6 A
˚
resolution’, Nature, 405, 648. Copyright
(2000) Macmillan Magazines Ltd.
COLOUR PLATES
A
B
Plate 3 The KcsA channel. (A) Ribbon diagram of the tetrameric complex embedded in the membrane. The
selectivity filter is at the top of the figure surrounded by the four ‘turrets’. (B) Electron density diagram of the K
+
-
selectivity filter at 2.0 A
˚
resolution. Four K
+
ions are caught in the filter (green spheres) and water molecules (red
spheres) associated with K
+
ions can be seen outside (top of figure) and inside (bottom of figure) the membrane.
D80 (Asp
80
) and E71 (Glu
71
) identify amino acid residues. Part A reprinted with permission from Doyle, D. A. et al.,

1998, ‘The structure of the potassium channel: molecular basis of K
+
conduction and selectivity’, Science, 280 , 73.
Copyright (1998) American Association for the Advancement of Science. Part B reprinted with permission from
Zhou, Y, et al., 2001, ‘Chemistry of ion coordination and hydration revealed by a K
+
channel-Fab complex at 2.0 A
˚
resolution’, Nature, 414, 45. Copyright (2001) Macmillan Magazines Ltd.
ELEMENTS OF MOLECULAR NEUROBIOLOGY
A
B
Plate 4 The MscL channel. (A) Ribbon diagram of the mechanosensitive channel from M. tuberculosis.
(TbMscL). Side view on left; extracellular view on right. the five subunits are individually coloured and the N and C
terminals of one of the subunits (cyan coloured) and its transmembrane helices (TM1, TM2) are labelled. Note that
only the upper part of the molecule is embedded in the membrane. (B) Cylinder models of the MscL channel of E.
coli (EcoMscL). Upper row shows the molecule from the side, lower row looking upward from the periplasm. The
figure shows (from left to right) closed/resting conformation; closed/expanded conformation; open conformation. The
five subunits are (as in (A) above) differently coloured and only one (blue) is labelled. The TM helices are labelled M1
and M2 and the other helices S1, S2, S3. The C and N terminals of the blue subunit are also indicated. Horizontal
lines show the approximate position of the membrane. When the membrane is stretched the S1 helices are, at first,
dragged over to plug the incipient pore (middle figures), if stretching continues the S1 helices are ultimately pulled
away to open a large passageway (right hand figures). Part A reprinted with permission from Chang, G. et al., 1998,
‘Structure of the MscL homolog from Mycobacterium tuberculosis: A gated mechanosensitive channel’, Science,
282, 2224. Copyright (1998) American Association for the Advancement of Science. Part B reprinted with
permission from Sukharev, S. et al., 2001, ‘The gating mechanism of the large mechanosensitive channel MscL’,
Nature, 409, 721. Copyright (2001) Macmillan Magazines Ltd.
1
INTRODUCTORY ORIENTATION
Origins of molecular neurobiology – outline of nervous systems – significance of invertebrates –

developmental introduction to vertebrate nervous systems – cellular structure of brains –
neurons – glia – nature and organisation of synapses – organisation of neurons in the
mammalian brain – complexity of the cortex – modular structure – columns – integrality
The nervous system and, in particular, the brain is
commonly regarded as the most complex and
highly organised form of matter known to man.
Indeed it has sometimes been said that if the brain
were simple enough for us to understand, we
ourselves would be too simple to understand it!
This, of course, is a play on the word ‘simple’ and,
moreover, seems in the long perspective of scientific
history unnecessarily pessimistic.
Our task in this text is, anyway, far less
ambitious. We do not hope to achieve any total
‘understanding’ of the brain in the following pages.
All we shall attempt is an exposition of the elements
of one very powerful approach to its structure and
functioning – the molecular approach. It is always
important to bear in mind that this is but one of
several approaches. A full understanding (if and
when that comes) will emerge from a synthesis of
insights gained from many different disciplines and
from different techniques applied at different
‘levels’ of the brain’s structure and functioning
(see Figu re A, Appendix 1). In this respect the
brain is very like a ravelled knot. Indeed Arthur
Schopenhauer, in the nineteenth century, famously
alluded to the mind/brain problem as ‘the world
knot’.
Molecular neurobiology is a young subject. But,

like all science, its roots can be traced far back into
the past. It has emerged from the confluence of a
number of more classical specialisms: neuro-
physiology, neurochemistry, neuroanatomy. While
neurophysiology and neuroanatomy may be traced
back into the mists of antiquity, neurochemistry
originated comparatively recently. Thudichum is
generally regarded as having founded the subject in
1884 with the publication of his book The Chemical
Constitution of the Brain. This comparatively recent
origin has, of course, to do with the great difficulty
of studying the chemistry of living processes,
especially those occurring in the brain. Biochemis-
try itself, although originating in the nineteenth
century, only began to gather momentum in the
middle decades of the twentieth.
Perhaps the decisive moment came almost
exactly midway through the twentieth century
when, in 1953, James Watson and Francis Crick
published their celebrated solution to the structure
of DNA. From this date may be traced a vast and
still explosively developing science – molecular
biology – which has informed the work of all
biologists, not least those who have been concerned
with the biology of the nervous system.
Molecular biology itself originated by the
coming together of two very different strands of
scientific endeavour. It combined the work of
biophysicists interested in the molecular structure
Elements of Molecular Neurobiology. C. U. M. Smith

Copyright
 2002 John Wiley & Sons, Ltd.
ISBNs: 0-470-84353-5 (HB); 0-471-56038-3 (PB)
Elements of Molecular Neurobiology. C. U. M. Smith
Copyright
 2002 John Wiley & Sons, Ltd.
ISBNs: 0-470-84353-5 (HB); 0-471-56038-3 (PB)
of biological materials, especially the structure of
proteins and nucleic acids, with the work of
geneticists, especially microbial geneticists, con-
cerned with understanding the nature of heredity
and the genetic process. Although molecular biol-
ogy has undergone a huge development and
diversification in the decades since 1953 these
concerns still remain at its core. The conjunction
of these two apparently dissimilar interests has led
in the 1980s and 1990s to a new high-tech
industry – biotechnology. Biology is no longer a
descriptive subject: the understandings flowing
from molecular biology are beginning to allow us
to manipulate living material in powerful and
fascinating ways. The first company to be founded
explicitly to exploit this manipulative ability
(Genentech) was valued at over $200 million by
the New York Stock Exchange in 1981; in 1987 the
world-wide sales of genetically engineered chemi-
cals were upwards of $700 million and, although
few gene companies have yet to show a profit
(except those manufacturing scientific instruments),
a hundred-billion-dollars-a-year industry is confi-

dently predicted for the twenty-fi rst century.
This new-found ability to manipulate has very
recently begun to be applied to the nervous system.
It is this development which lies at the root of the
subject to be outlined in this book – molecular
neurobiology. It is beginning to be possible to
manipulate basic features of the nervous system
both to aid understanding and, as knowledge is
often power, to bring about desirable change. The
brain is man’s most precious possession and to a
large extent makes him what he is and can become.
The birth of molecular neurobiology thus brings
prospects of enormous practical importance – for
good or ill. We have every reason to study it
carefully.
1.1 OUTLINE OF NERVOUS
SYSTEMS
There are many excellent accounts of the nervous
system. Some recommended texts are indicated in
the Bibliography. This introductory section is
merely designed to present some of the salient
points in a convenient form.
It is possible to argue that the nervous system
developed to serve the senses. Heterotrophic forms
such as animals ne cessarily have to seek out their
nutriment. The information gathered by the sen-
sory cells has to be collated and appropriate
responses computed. Hence the nervous system. It
also follows that, to an extent, the nature of the
nervous system which an animal possesses reflects

its life-style. Active animals develop large and
elaborate nervous systems; quiescent forms make
do with minimal nervous tissue. In general animals
cannot afford to carry more nervous system than
they actually need.
A glance at any zoology text is enough to remind
us of the huge variety of animals with which we
share the globe. It follows that there is a huge
number of different nervous system designs. Many
of these designs provide opportunities to investi-
gate neurobiological problems which are difficult to
solve in mammalian systems. An awareness of the
wealth of different systems presented by the animal
kingdom is a valuable asset for any neurobiologist
and, in particular, as we shall see, for any molecular
neurobiologist.
One general design feature is found in all nervous
systems above the level represented by the Porifera
(sponges) and Cnidaria (jelly fish, sea anemones,
hydroids). This is the separation of the nervous
system into a central ‘computing’ region and a
peripheral set of nerve fibres carrying information
to and from the centre. In the chordates the ‘central
region’, or central nervous system (CNS), consists of
the brain and spinal cord (Figure 1.1), and the
peripheral nervous system (PNS) consists of the
cranial and spinal nerves.
Other animals show other designs. Often we can
dimly discern evolutionary reasons for these differ-
ences. One major difference which is worth men-

tioning at this stage is that which obtains between
the chordates and the great assemblage of hetero-
geneous forms grouped for convenience under the
title ‘invertebrates’ or ‘animals without backbones’.
The CN S of chordates (this phylum includes all the
vertebrates) always develops in the dorsal position
whilst that of the invertebrates develops in the
ventral position (Figure 1.2). It is believed that this
striking difference is due to the fact that chordates
originated in the warm upper layers of palaeozoic
seas whilst invertebrates originated as forms crawl-
ing over the bottoms of equally or yet more ancient
seas and lagoons. The major sensory input for the
chordates would have thus come from above, that
for the invertebrates from below. Hence the
2
ELEMENTS OF MOLECULAR NEUROBIOLOGY
different positioning of their central nervous sys-
tems. We shall see, in later chapters, that evolu-
tionary considerations also play a significant role in
molecular neurobiology, indeed they form one of
the major themes of this book. Here, as elsewhere,
they help us answer the question of why things are
as they are.
Whilst the nervous systems of all animal phyla
are of great interest, neurobiologists have tended to
concentrate their attention on a few phyla in
particular. The phylum Nematoda (roundworms)
provides forms with extremely simple nervous
systems and quick generation times. The worm

Caenorhabditis elegans has provided a nervous
system simple enough (just 302 neurons subdivided
into 118 classes, some 5600 synapses and about
2000 neuromuscular junctions) to have its genetics,
development and anatomy mapped in its entirety.
This very simple nervous system nevertheless
supports a wide variety of behaviours. Neuro-
biologists using genetics, laser ablation and chemi-
cal analysis are well on the way towards running
these behavioural patterns into the neural ‘wiring
diagram’. The phylum Annelida (segmented worms)
contains forms such as the leech Hirudo whose
ganglionated CNS has also provided a simple
system for intensive investigation. The phylum
Mollusca has also been much studied. The squid
Loligo has provided invaluable experimental pre-
parations. More recently, the sea-hare Aplysia has
been the focus of a great deal of interest at the
molecular level. The phylum Arthropoda provides
many insect and crustacean preparations, including
perhaps the simplest system of all, the 28-neur on
crustacean stomatogastric ganglion which controls
INTRODUCTORY ORIENTATION 3
Figure 1.1 Human brain and spinal cord showing
roots of the spinal nerves. The central nervous system
is viewed from behind. The posterior view of the brain
shows the two large cerebral hemispheres resting on
top of the two cerebellar hemispheres. Pairs of spinal
nerves emerge between the vertebrae of each segment
of the cord (8 cervical, 12 thoracic, 5 lumbar and

5 sacral). The spinal cord ends between the twelfth
thoracic and the second lumbar segment and continues
as the cauda equina. In the figure the latter has been
fanned out on the left and left undisturbed on the right.
C1¼ first cervical vertebra; T1¼ first thoracic vertebra;
L1¼ first lumbar vertebra; S1¼ first sacral vertebra.
From Warwick and Williams (1973), Gray’s Anatomy,
reproduced by permission of Churchill Livingstone,
Edinburgh.
the rhythmical action of the gastric mill, whilst
Limulus, the ‘king’ or horsehoe ‘crab’ (in fact an
arachnid), has been much studied by
visual physiologists. In recent years the fruit fly
Drosophila, long a favourite with geneticists, has
become central to those interested in the genetics
and embryology of the nervous system. The ‘mush-
room bodies’ or corpora pedunculata, in its nervous
system, deeply involved in olfactory learning and
memory, consist of only 2500 neurons. Finally, of
course, we come to the phylum Chordata – the
phylum to which we, along with all the other
vertebrates, belong. Here many species have pro-
vided important opportunities for neurobiological
research. The simplest of all, the larva of the
urochordate Ciona intestinali s, consists of only
2600 cells and its nervous system, which controls
typical sinuous swimming movements, is made up
of fewer than 100 cells. Thre e vertebrates deserve
special mention: Xenopus laevis, the South African
clawed frog; Danio rerio, the zebra fish; and Mus

musculus, the mouse. Each of these species has
proved valuable for the investigation of particular
neurobiological problems.
Although disinterested curiosity has always
motivated scientists, and animal nervous systems
are worth investigating in their own right ‘because
they’re there’, the major thrust of neurobiological
endeavour (and its funding agencies) has always
been to illuminate the workings of the human
brain. Invertebrates, as indicated above, frequently
provide particularly convenient preparations for
investigating problems which are difficult to tackle
in mammalian and a fortiori human brains, but at
the end of the day it is an understanding of the
human nervous system which is sought.
Further information about invertebrate nervous
systems can be obtained from the books listed in
the Bibliography. Here we shall confine ourselves
to a very brief re
´
sume
´
of the mammalian and,
especially, the human CNS.
1.2 VERTEBRATE NERVOUS
SYSTEMS
One of the best ways of getting a grip on the
structure of the vertebrate nervous system is to
follow its development. There has been an enor-
mous increase in our understanding of this process

in the last decade or so. This new understanding
often goes under the provocative title ‘evo-devo’.
This draws attention to the fact that investigations
of early developmental processes often throw
light on early phases of animal evolution. An
4
ELEMENTS OF MOLECULAR NEUROBIOLOGY
Figure 1.2 (A) Schematic sagittal section through
idealised chordate to show position of the CNS. (B)
Schematic diagram to show the position of the CNS
in a typical non-chordate. It should be borne in mind
that whereas chordates form a homogeneous
group, sharing a common design principle, non-
chordates are many and various. The schematic
diagram in (B) fits the worms and the Arthropoda
but is quite inappropriate for radial symmetric
groups such as the Cnidaria and Echinodermata
and can only with difficulty accommodate the
Mollusca.
analogy might be drawn with fundamental physics.
Research in high energy physics, at CERN and
elsewhere, assists astrophysicists in their researches
on the beginnings of the universe and vice versa.
We shall look more deeply at the developmental
genetics of the vertebrate nervous system in
Chapter 18. Here a quick sketch will suffice.
The vertebrate CNS originates as a longitudinal
strip of neurectoderm (¼ neural plate) which
appears on the dorsal surface of the very early
embryo. Does embryology recapitulate phylogeny

here as Ernst Haeckel long ago suspected? This
strip of neurectoderm soon sinks beneath the
surface of the embryo, first forming a gutter and
then rolling up to form a neural tube. At the
anterior end of this tube three swellings (or vesicles)
appear (Figure 1.3). These constitute the embryonic
fore-, mid- and hindbrains (prosencephalon, mesen-
cephalon and rhombencephalon). Again, does
embryology recapitulate phylogeny? All bilaterally
symmetrical animals move with one end of their
bodies entering new environments first. It follows
that sense organs to pick up information from and
about the environment tend to be concentrated on
that anterior end. It also follows that specialisation
of these sense organs to pick up the principal types
of information is likely to occur. Thus animals
tend to develop detectors for chemical substances
(chemoreceptors), electromagnetic radiation
(photoreceptors) and mechanical disturbance
(mechanoreceptors). It turns out that the three
primary vesicles are initially concerned with the
analysis of these three primary senses: olfaction,
vision (although the eye itself originates from the
posterior part of the forebrain) a nd vibration,
respectively.
As embryological development continues, the
early three-vesicle brain subdivides to form a five-
vesicle structure. This happens by the hindbrain
(the rhombencephalon) subdividing into a posterior
myelencephalon and a more anterior metencephalon

and the forebrain (the prosencephalon) also sub-
dividing into an anterior telencephalon and a more
posterior thalamencephalon (or diencephalon). The
midbrain remains undivided. The cavity within the
metencephalon now expands somewhat to form the
fourth ventricle joined by a narrow canal, the iter,
to the third ventricle within the thalamencephalon,
which in turn communicates with two lateral
ventricles within the cerebral hemispheres which
develop from the telencephalon.
Further developm ent of the brain does not
involve any further major subdivision. The funda-
mental architecture of the brain remains essentially
as shown in Figure 1.4. Great developments,
however, oc cur principally in the roof of this five-
vesicle structure. From the roof of the metence-
phalon grows the cerebellum. This structure, as it is
involved in the orchestration of the muscles to
produce smooth behavioural movements, is always
large in active animals. In primates, such as
ourselves, it is thus extremely well developed.
Survival of thirty million years or so of arboreal
life demanded an extreme of neuromuscular coor-
dination. In ourselves it is the second largest part of
the brain. Associated with the cerebellum, in the
floor of the metencephalon, is an other large
structure, the pons. The pons acts as a sort of
junction box where fibres to and from the cerebel-
lum can interact with fibres running to and from
other parts of the CNS.

The roof of the midbrain forms the tectum in the
lower vertebrates. It is to this region, as indicated
above, that the visual information is directed. This
information is so important that, in the fish and
amphibia, it attracts fibres carrying information
INTRODUCTORY ORIENTATION 5
Figure 1.3 Embryology of the vertebrate
brain: idealised sagittal section of three-
vesicle stage.
from the other senses so that the tectum becomes
the major brain area for association and cross-
correlation of sensory information. The tect um in
these animals is perhaps the most important part of
the brain. In the mammals, however, this impor-
tance is lost. Visual information, as we shall see, is
mostly directed to the cerebral cortex. The roof of
the midbrain in mammals is thus quite poorly
developed. Four smallish swellings can be detected
there – two inferior and two superior colliculi. The
inferior colliculi are part of the auditory pathway
from the cochlea whilst the superior colliculi still
play a small, though important, role in the analysis
of visual information.
It is the forebrain, however, which has under-
gone the most dramat ic development in the mam-
mals and especially in the primates. A number of
important nerve centres are located in the thala-
mencephalon (the lateral geniculate, medial genicu-
late and thalamic nuclei) which act as ‘way stations’
for fibres running from the senses towards the

cerebrum. From the roof of this region grows the
pineal organ (in the mammals an important endo-
crine gland of which we shall have more to say
later), and from the floor (the hypothalamus) grows
the neural part of the pituitary.
But by far the greatest development occurs in the
telencephalon. This grows enormously and
becomes reflected back over the thalamencephalon
which it ultimately covers and encloses (Greek
thalamos¼ inner room) (Figure 1.5). It divides into
two great ‘hemispheres’, the cerebral hemispheres ,
each of which contains a ventricle – the lateral
ventricle. In the mammals information from all the
senses is brought to the cerebrum and it is here that
it is collated and analysed.
In Homo sapiens the cerebrum has become
gigantic and overgrows and obscures the other
(more ancient) regions of the brain. The anatomy is
also made more difficult to understand by man’s
assumption of an upright stance. This causes the
brain to bend through nearly a right angle – a
characteristic called cerebral flexure (Figure 1.6).
One other feature of the general anatomy of the
human brain should be mentioned. This is the
existence of a series of structures which lie between
the cerebrum and the thalamencephalon. These
structures constitute the limbic system (Figure
1.7) – so called from the Latin limbus meaning
‘edge’ or ‘border’, as in the Dantean limbo which
was conceived as a region between earth and hell.

The limbic system is not only situated between the
cerebrum and the thalamencephalon but is also
believed to be involved in emotions and emotional
responses. Some have therefore seen this region as a
relic from our infra-human evolutionary past.
6
ELEMENTS OF MOLECULAR NEUROBIOLOGY
Figure 1.4 Embryology of the vertebrate
brain: idealised sagittal section of five-vesicle
stage. The figure shows the telencephalon
growing backwards over the surface of the
thalamencephalon. This only occurs in animals
which develop large cerebral hemispheres,
such as mammals. From the roof of the
thalamencephalon grows the pineal gland while
from its floor develops the neural part of the
pituitary. The cerebellum grows from the roof of
the metencephalon while the floor of this region
expands to form the pons. The whole structure
contains a cavity continuous with the central
canal of the spinal cord and filled with cerebral
spinal fluid (CSF).