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Alexei Verkhratsky is Professor of Neurophysiology and Chairman of the Division of Neuroscience at the University of Manchester, UK.
Arthur Butt is Professor of Cellular Neurophysiology, Department of Pharmacy and Biomedical Sciences, University of Portsmouth, UK.
About the Authors xxi
Abbreviations xxv
About the Companion Website xxxii
1 History of Neuroscience and the Dawn of Research in Neuroglia 1
1.1 The miraculous human brain: localising the brain functions 1
1.2 Cellular organisation of the brain 10
1.3 Mechanisms of communications in neural networks 14
1.3.1 Electrical/ionic nature of excitability 14
1.3.2 Chemical signalling between neural cells 26
1.4 The concept of neuroglia 27
1.5 Beginning of the modern era 47
1.6 Concluding remarks 49
References 49
2 General Overview of Signalling in the Nervous System 59
2.1 Intercellular signalling: wiring and volume modes of transmission 59
2.2 Cellular signalling: receptors 62
2.3 Intracellular signalling: second messengers 67
2.4 Calcium signalling 67
2.4.1 Cellular Ca2þ
regulation 69
2.5 Concluding remarks 72
3 Neuroglia: Definition, Classification, Evolution, Numbers,
Development 73
3.1 Definition of neuroglia as homeostatic cells of the nervous system 74
3.2 Classification 75
3.3 Evolution of neuroglia 76
3.3.1 Evolution of astrocytes 79
(i) Nematoda: neuroglia in Caenorhabditis elegans 79
(ii) Annelida: astroglia in leech 81
(iii) Arthropoda: astrocytes in Drosophila and other insects 83
(iv) Neuroglia in early Deuterostomia (Hemichordata and
Echinodermata) 85
(v) Neuroglia in low vertebrates 85
(vi) Glial advance in higher vertebrates 86
3.3.2 Evolution of myelination 89
3.3.3 Evolution of microglia 92
3.4 Numbers: how many glial cells are in the brain? 93
3.5 Embryogenesis and development of neuroglia in mammals 96
3.5.1 Macroglial cells 96
3.5.2 Astroglial cells are brain stem cells 98
3.5.3 Peripheral glia and schwann cell lineage 98
3.5.4 Microglial cell lineage 99
3.6 Concluding remarks 99
References 100
4 Astroglia 105
4.1 Definition and heterogeneity 107
4.2 Morphology of the main types of astroglia 113
4.3 How to identify astrocytes in the nervous tissue 119
4.4 Astroglial syncytial networks 120
4.4.1 Gap junctions, connexons and connexins 120
4.4.2 Astroglial networks 123
4.5 Physiology of astroglia 125
4.5.1 Membrane potential and ion distribution 125
4.5.2 Ion channels 126
(i) Potassium channels 126
(ii) Voltage-operated sodium channels (Nav) 130
(iii) Calcium channels 131
(iv) Transient receptor potential or TRP channels 131
(v) Anion/chloride channels 131
(vi) Aquaporins 132
4.5.3 Receptors to neurotransmitters and neuromodulators 133
(i) Glutamate receptors 137
(ii) Purinoceptors 141
(iii) g-aminobutiric acid receptors (GABA) receptors 146
(iv) Glycine receptors 148
(v) Acetylcholine receptors 148
(vi) Adrenergic receptors 148
(vii) Serotonin receptors 149
(viii) Histamine receptors 149
(ix) Cannabinoid receptors 149
(x) Neuropeptide receptors 149
(xi) Cytokine and chemokine receptors 150
(xii) Complement receptors 151
(xiii) Platelet-activating factor receptors 151
(xiv) Thrombin receptors 151
(xv) Ephrin receptors 151
(xvi) Succinate receptors 152
4.5.4 Astroglial membrane transporters 152
(i) ATP-dependent transporters 153
(ii) Secondary transporters 154
4.5.5 Calcium signalling in astroglia 156
(i) Endoplasmic reticulum provides for Ca2+ excitability
of astrocytes 156
(ii) Store-operated Ca2þ
entry in astrocytes 158
(iii) Ionotropic Ca2þ
permeable receptors in astrocytes 158
(iv) Sodium/calcium exchanger in astroglial Ca2þ
signalling 159
(v) Mitochondria in astroglial Ca2þ
signalling 159
(vi) Calcium waves in astrocytes 159
4.5.6 Sodium signalling in astrocytes 164
4.5.7 Release of neurotransmitters and neuromodulators from astroglia 165
(i) Exocytotic release of neurotransmitters from astrocytes 167
(ii) Diffusional release of neurotransmitters from astrocytes 172
(iii) Transporter-mediated neurotransmitter release from
astrocytes 173
(iv) Astrocytes as a main source of adenosine in the CNS 174
(v) Physiological role of astroglial release
of neurotransmitters 174
4.6 Functions of astroglia 175
4.6.1 Developmental function: neurogenesis and gliogenesis 176
(i) Embryonic neurogenesis and gliogenesis 176
(ii) Neurogenesis and gliogenesis in the adult brain 178
4.6.2 Neuronal guidance 179
4.6.3 Regulation of synaptogenesis and control of synaptic
maintenance and elimination 182
4.6.4 Structural function: astrocytes define the micro-architecture
of the grey matter and create neurovascular units 185
4.6.5 Structural function: astrocytes and the brain-blood barrier 186
4.6.6 Astrocytes regulate brain microcirculation 192
4.6.7 Brain energetics and neuronal metabolic support 195
4.6.8 Astroglia and neuroimaging 200
4.6.9 Ion homeostasis in the extracellular space 200
(i) Astrocytes and extracellular potassium homeostasis 200
(ii) Astrocytes and chloride homeostasis 204
(iii) Astrocytes and extracellular Ca2þ
204
(iv) Astrocytes and regulation of pH 205
(v) Astrocytes and zinc homeostasis 206
4.6.10 Astrocytes and homeostasis of reactive oxygen species 206
4.6.11 Water homeostasis and regulation of the extracellular
space volume 207
(i) Regulation of water homeostasis 207
(ii) Regulatory volume decrease in astrocytes 208
(iii) Redistribution of water during neuronal activity and
dynamic regulation of the extracellular space 208
4.6.12 Neurotransmitters homeostasis 209
(i) Astroglia control glutamate homeostasis and
glutamatergic transmission in the CNS 209
(ii) Astroglia and GABA-ergic transmission 213
(iii) Astroglia and adenosine homeostasis 214
4.6.13 Astroglia in synaptic transmission 215
(i) The astroglial synaptic compartment: concept of
the tripartite synapse 215
(ii) The astroglial synaptic compartment: concept of
the astroglial cradle 219
(iii) Morphological plasticity of the astroglial synaptic
compartment 221
(iv) What is the role of astroglia in regulation of synaptic
transmission? 222
4.6.14 Astroglia and central chemoception of pH and CO2 224
4.6.15 Astrocytes in regulation of systemic sodium homeostasis 224
4.6.16 Astroglia and glucose sensing 225
4.6.17 Astroglia and circadian rhythms 226
4.6.18 Astroglia and sleep 227
4.6.19 Astroglia and control of reproduction 228
4.6.20 M€uller glial cells as light guides in retina 228
4.6.21 Astroglia in ageing 228
4.6.22 Astrocytes as a cellular substrate of memory and
consciousness? 230
4.7 Concluding remarks 231
References 231
5 Oligodendrocytes 245
5.1 Oligodendrocyte anatomy 247
5.1.1 The generalised structure of a myelinating oligodendrocyte 247
5.1.2 Subtypes of myelinating oligodendrocytes 249
5.1.3 Non-myelinating oligodendrocytes 251
5.2 Myelin structure and function 252
5.2.1 Myelin and saltatory conduction 252
5.2.2 Oligodendrocyte-axon interactions and nodes of Ranvier 256
5.2.3 Myelin structure and metabolism 257
5.2.4 Myelin biochemistry 258
(i) Lipids 258
(ii) Proteins 261
5.2.5 Myelin transport 265
5.3 Physiology of oligodendrocytes 266
5.3.1 Voltage-operated ion channels 270
(i) Outwardly rectifying potassium channels 270
(ii) Inward rectifier potassium channels (Kir) 271
(iii) Voltage-operated sodium channels (Nav) 272
(iv) Voltage-operated calcium channels (VOCC, Cav) 272
(v) Chloride and acid-sensing ion channels (ASIC) 273
5.3.2 Glutamate receptors 273
(i) Ionotropic glutamate receptors (iGluRs) 273
(ii) Metabotropic glutamate receptors (mGluRs) 275
5.3.3 Purinergic receptors 275
(i) P1 purinergic receptors 275
(ii) P2X receptors 276
(iii) P2Y receptors 276
5.3.4 GABA receptors 277
5.3.5 Other neurotransmitter receptors 278
5.3.6 Transporters and exchangers 279
5.3.7 Gap junctions 279
5.3.8 Intracellular calcium 280
5.4 Oligodendrocyte development 283
5.4.1 Developmental origins of oligodendrocytes 284
5.4.2 Stages of oligodendrocyte differentiation 284
5.4.3 Trophic factors and oligodendrocyte differentiation 286
5.4.4 Regulation of oligodendrocyte differentiation 288
5.4.5 Axoglial interactions regulating oligodendrocyte
differentiation and myelination 293
5.4.6 Downstream signalling cascades that regulate
oligodendrocyte differentiation and myelination 297
5.5 Concluding remarks 299
References 299
6 NG2-glial Cells 321
6.1 Definition of NG2-glia 321
6.2 Structure of NG2-glia 324
6.2.1 Identification 324
6.2.2 Morphology and distribution 325
6.2.3 Relationship of NG2-glia with neuroglial domains 326
6.2.4 NG2-glia and synapses 326
6.3 Physiology of NG2-glia 327
6.3.1 Membrane properties 328
6.3.2 Gap junctional coupling 328
6.3.3 Voltage-operated ion channels 330
6.3.4 Neurotransmitter receptors 330
6.3.5 Neurone-NG2-glial cell signalling at synapses 331
6.4 Proliferation of NG2-glia and generation of oligodendrocytes 332
6.4.1 Normal adult brain 332
6.4.2 Are NG2-glia multipotent stem cells? 333
6.4.3 Response of NG2-glia to injury and demyelination 333
6.5 Relationship between NG2-glia and CNS pericytes 333
6.5.1 Identification of pericytes 333
6.5.2 Developmental origin of pericytes 334
6.5.3 Pericytes are multipotent stem cells in the adult brain 336
6.6 Evolution of NG2-glia 336
6.7 Concluding remarks 337
References 337
7 Microglia 343
7.1 Definition of microglia 344
7.2 Microglial origin and development 345
7.3 Morphology of microglia 345
7.3.1 Morphology in the healthy tissue: resting or survelliant phenotype 345
7.3.2 Morphology in pathological tissue: activated phenotype 349
7.3.3 Morphology in the dish 350
7.3.4 Identification of microglial cells in neural tissues 351
7.4 General physiology of microglia 351
7.4.1 Membrane potential and ion distribution 351
7.4.2 Ion channels in microglia 352
(i) Sodium channels 352
(ii) Calcium-permeable channels 352
(iii) Potassium channels 357
(iv) Anion channels 358
(v) Proton channels 358
7.4.3 Calcium signalling in microglia 358
7.4.4 Neurotransmitter receptors 360
(i) Purinoceptors 360
(ii) Glutamate receptors 363
(iii) GABA receptors 363
(iv) Acetylcholine receptors 364
(v) Adrenergic receptors 364
(vi) Dopamine receptors 364
(vii) Serotonin receptors 364
7.4.5 Receptors for neurohormones and neuromodulators 364
7.4.6 Cytokines and chemokines receptors 367
7.4.7 Pattern-recognition receptors 369
7.4.8 Other receptor systems 370
7.4.9 Microglial plasmalemmal transporters 371
7.5 Microglial migration and motility 372
7.6 Physiological functions of microglia: role in synaptic transmission
and plasticity 373
7.7 Microglia in ageing 375
7.8 Concluding remarks 375
References 376
8 Peripheral Glial Cells 381
8.1 Peripheral nervous system 382
8.1.1 Basic structure 382
8.1.2 Development 385
8.1.3 The CNS-PNS interface 387
(i) Structure of the CNS-PNS interface 387
(ii) Development of the CNS-PNS interface 389
(iii) CNS-PNS interface in degeneration and regeneration 390
8.2 Schwann cells 390
8.2.1 Schwann cell subtypes 391
8.2.2 Development of Schwann cells 394
(i) Stages of Schwann cell differentiation 394
(ii) Regulation of Schwann cell differentiation 396
(iii) Control of myelination 397
8.2.3 Axoglial interactions and myelination 397
(i) The Schwann cell basal lamina 399
(ii) Organisation of nodes of Ranvier in the PNS 399
(iii) Schwann cell perinodal microvilli 399
8.2.4 PNS myelin structure and biochemistry 400
(i) Lipids 401
(ii) Proteins 401
8.2.5 Physiology of Schwann Cells 403
(i) Ion channels and neurotransmitter receptors 403
(ii) Ca2þ
signalling in Schwann cells 406
(iii) Schwann cells and pain 407
8.3 Satellite glial cells 407
8.3.1 Organisation of sensory and autonomic ganglia 407
8.3.2 Satellite glia in sensory and autonomic ganglia 408
8.3.3 Physiology of satellite glia 408
(i) Electrical properties 408
(ii) Homeostatic function 409
(iii) Ca2þ
signalling 409
(iv) Other receptors in SGCs 409
(v) Neurotrophic function of SGC 409
8.3.4 Injury response of satellite glia 410
8.3.5 Sensory satellite glia and pain 411
8.4 Enteric glia 412
8.4.1 Organisation of the enteric nervous system 412
8.4.2 Development of enteric glia 413
8.4.3 Structure of enteric glia 413
8.4.4 Physiology of enteric glia 415
(i) Electrical properties 415
(ii) Ion channels and neurotransmitter receptors 415
(iii) Ca2þ
signalling 416
8.4.5 Functions of EGCs 416
(i) Homeostatic functions 416
(ii) Barrier function 417
(iii) Immune functions 418
(iv) Enteric glia in intestinal diseases 418
8.5 Olfactory ensheathing cells (OECs) 418
8.5.1 Organisation and structure of OECs 418
8.5.2 Physiology of OECs 419
(i) Electrical properties 419
(ii) Ca2þ
signalling 420
8.5.3 OECs facilitate olfactory neurogenesis throughout life 420
8.5.4 OECs and regeneration 421
8.5.5 OECs and remyelination 422
8.6 Concluding remarks 422
References 423
9 General Pathophysiology of Neuroglia 431
9.1 Neurological disorders as gliopathologies 431
9.2 Reactive astrogliosis 433
9.3 Wallerian degeneration 439
9.4 Excitotoxic vulnerability of oligodendrocytes: the death of white matter 442
9.5 Activation of microglia 444
9.5.1 Pathological potential of activated microglia 449
9.6 Concluding remarks 449
References 450
10 Neuroglia in Neurological Diseases 453
10.1 Introduction 454
10.2 Genetic astrogliopathology: Alexander disease 456
10.3 Stroke and ischaemia 458
10.3.1 Glial cell death during ischaemia 460
10.3.2 Astroglia protect the brain against ischaemia 463
10.3.3 Astrocytes may exacerbate brain damage in ischaemia 465
10.3.4 Oligodendrocytes and microglia in stroke 467
10.4 Migraine and spreading depression 467
10.5 CNS oedema 469
10.5.1 Traumatic oedema 470
10.5.2 Ischaemic oedema 470
10.5.3 Oedema in hepatic encephalopathy 471
10.5.4 Hyponatremia 471
10.6 Metabolic disorders 471
10.6.1 Hepatic encephalopathy 471
10.6.2 Congenital glutamine deficiency with glutamine
synthetase mutations 472
10.6.3 Pyruvate carboxylase deficiency 472
10.6.4 Niemann-pick type C disease 473
10.6.5 Aceruloplasminemia 473
10.7 Toxic encephalopathies 473
10.7.1 Methylmercury toxic encephalopathy 473
10.7.2 Lead toxic encephalopathy 474
10.7.3 Manganese neurotoxicity 474
10.7.4 Aluminium toxic encephalopathy 474
10.8 Neurodegenerative diseases 474
10.8.1 Post-stroke dementia 475
10.8.2 Amyotrophic lateral sclerosis 477
10.8.3 Wernicke encephalopathy 479
10.8.4 Fronto-temporal, thalamic, HIV-associated and other
non-Alzheimer’s type dementias 479
10.8.5 Alzheimer’s disease (AD) 480
(i) Astrogliosis and astroglial degeneration in AD 482
(ii) Astroglia and b-amyloid 483
(iii) The neuro-vascular unit in AD: role for astrocytes 483
(iv) Metabolic remodelling of astroglia in AD 484
(v) Microglia in AD 484
10.8.6 Parkinson’s disease 485
10.8.7 Huntington’s disease 486
10.8.8 Infantile neuroaxonal dystrophy 486
10.8.9 Nasu-Hakola disease: microglial pre-senile dementia 486
10.9 Leukodystrophies 487
10.9.1 Megalencephalic leukoencephalopathy with
subcortical cysts 487
10.9.2 Vanishing white matter disease 487
10.10 Epilepsy 488
10.11 Psychiatric diseases 490
10.12 Autistic disorders 491
10.12.1 Autism 491
10.12.2 Fragile X syndrome 491
10.12.3 Rett syndrome 491
10.13 Neuropathic pain 492
10.14 Demyelinating diseases 494
10.14.1 Multiple sclerosis 494
10.14.2 Neuromyelitis optica 496
10.15 Infectious diseases 496
10.15.1 Bacterial and viral infections 496
10.15.2 Human immunodeficiency virus (HIV) infection 497
10.15.3 Human T-lymphotropic virus type-1 498
10.15.4 Human herpes virus-6 499
10.16 Peripheral neuropathies 499
10.16.1 Hereditary neuropathies 499
10.16.2 Acquired inflammatory neuropathies 500
10.16.3 Diabetic neuropathies 500
10.16.4 Leprosy 501
10.17 Gliomas 501
10.17.1 Glial complications of glioma therapy 504
10.18 Concluding remarks 504
References 504
Author Index 513
Subject Index 517
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