Glial Neurobiology

A Textbook

Alexei Verkhratsky

University of Manchester

Arthur Butt

University of Portsmouth





John Wiley & Sons, Ltd

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Anniversary Logo Design: Richard J. Pacifico Library of Congress Cataloging in Publication Data Verkhratskii, A. N. (Aleksei Nestorovich)

Glial neurobiology: a textbook/Alexei Verkhratsky, Arthur Butt. p. ; cm.

Includes bibliographical references and index. ISBN 978-0-470-01564-3 (cloth: alk. paper) 1. Neuroglia. I. Butt, Arthur. II. Title.

[DNLM: 1. Neuroglia. WL 102 V519g 2007] QP363.2.V47 2007

611'.0188—dc22 2007015819

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A catalogue record for this book is available from the British Library

ISBN 978-0-470-01564-3 (HB) ISBN 978-0-470-51740-6 (PB)

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Dedicated to our Families


Preface xi

List of abbreviations xiii

PART I Physiology of Glia 1

1 Introduction to Glia 3

1.1 Founders of glial research: from Gabriel Valentin to Karl-Ludwig Schleich 3

1.2 Beginning of the modern era 11

1.3 Changing concepts: Glia express molecules of excitation 11

1.4 Glia and neurones in dialogue 12

2 General Overview of Signalling in the Nervous System 13

2.1 Intercellular signalling: Wiring and volume modes of transmission 13

2.2 Intracellular signalling 17

3 Morphology of Glial Cells 21

3.1 Astrocytes 21

3.2 Oligodendrocytes 24

3.3 NG2 expressing glia 26

3.4 Schwann cells 27

3.5 Microglia 28

4 Glial Development 29

4.1 Phylogeny of glia and evolutionary specificity of glial cells in human brain 29

4.2 Macroglial cells 32

4.3 Astroglial cells are brain stem cells 35

4.4 Schwann cell lineage 36

4.5 Microglial cell lineage 37

5 General Physiology of Glial Cells 39

5.1 Membrane potential and ion distribution 39

5.2 Ion channels 39

5.3 Receptors to neurotransmitters and neuromodulators 42

5.4 Glial syncytium - gap junctions 58

5.5 Glial calcium signalling 61

5.6 Neurotransmitter release from astroglial cells 71

5.7 Glial neurotransmitter transporters 76

5.8 Glial cells produce and release neuropeptides 79

5.9 Glial cell derived growth factors 80

6 Neuronal-Glial Interactions 83

6.1 Close apposition of neurones and astroglia: the tripartite synapse 83

6.2 Neuronal-glial synapses 85

6.3 Signalling from neurones to astrocytes 86

6.4 Signalling from astrocytes to neurones 89

6.5 Signalling between oligodendrocytes and neurones 90

6.6 Signalling between Schwann cells and peripheral nerves and nerve endings 90

PART II Glial Cells and Nervous System Function 93

7 Astrocytes 95

7.1 Developmental function - producing new neural cells 96

7.2 Developmental function - neuronal guidance 97

7.3 Regulation of synaptogenesis and control of synaptic maintenance and elimination 99

7.4 Structural function - creation of the functional microarchitecture of the brain 101

7.5 Vascular function - creation of glial-vascular interface (blood-brain barrier) and glia-neurone-vascular units 102

7.6 Regulation of brain microcirculation 105

7.7 Ion homeostasis in the extracellular space 106

7.8 Regulation of extracellular glutamate concentration 112

7.9 Water homeostasis and regulation of the extracellular space volume 114

7.10 Neuronal metabolic support 116

7.11 Astroglia regulate synaptic transmission 119

7.12 Integration in neuronal-glial networks 121

7.13 Astrocytes as cellular substrate of memory and consciousness? 121

8 Oligodendrocytes, Schwann Cells and Myelination 125

8.1 The myelin sheath 127

8.2 Myelination 141

8.3 Myelin and propagation of the action potential 148

PART III Glia and Nervous System Pathology 153

9 General Pathophysiology of Glia 155

9.1 Reactive astrogliosis 155

9.2 Wallerian degeneration 157

9.3 Activation of microglia 160

10 Glia and Diseases of the Nervous System 167

10.1 Alexander's disease 167

10.2 Spreading depression 167

10.3 Stroke and ischaemia 168

10.4 Cytotoxic brain oedema 178

10.5 Neurodegenerative diseases 180

10.6 Neuropathic pain 185

10.7 Demyelinating diseases 186

10.8 Infectious diseases 187

10.9 Peripheral neuropathies 190

10.10 Psychiatric diseases 192

10.11 Gliomas 194

Conclusions 197

Recommended literature 199

Author Index 207

Subject Index


Contemporary understanding of brain organization and function follows the neuronal doctrine, which places the nerve cell and neuronal synaptic contacts at the very centre of the nervous system. This doctrine considers glia as passive supportive cells, which are not involved in the informational exchange, and therefore secondary elements of the nervous system.

In the last few decades, however, our perception of the functional organization of the brain has been revolutionized. New data forces us to reconsider the main postulate of the neuronal doctrine - that neurones and synapses are the only substrate of integration in the central nervous system. We now learn that astroglial cells, which are the most numerous cells in the brain, literally control the naissance, development, functional activity and death of neuronal circuits. Astroglial cells are in fact the stem elements from which neurones are born. They also create the compartmentalization of the CNS and integrate neurones, synapses, and brain capillaries into inter-dependent functional units. Furthermore, astroglial cells form a functional syncytium, connected through gap junction bridges, which provides an elaborate intercellular communication route. This allows direct translocation of ions, metabolic factors and second messengers throughout the CNS, thereby providing a sophisticated means for information exchange. In a way the binary coded electrical communication within neuronal networks may be considered as highly specialized for rapid conveyance of information, whereas astroglial cells may represent the true substance for information processing, integration and storage. Will this truly heretical theory which subordinates neurones to glia be victorious at the end? Forthcoming years hold the answer.

When writing this book we have attempted to create a concise yet comprehensive account of glial cells and their role in physiology and pathology of the nervous system. We hope very much that this account may help the reader to discover a fascinating world of brain 'secondary' cells, which in fact are essential elements of the nervous system, whose functions and importance are yet to be fully appreciated.

Alexei Verkhratsky Arthur Butt

List of abbreviations










InsP3R K

adenylate cyclase acetylcholine acquired immunodeficiency syndrome a-amino-3-hydroxy-5-methyl-7-isoxazolepropionate aquaporins (water channels)

adenosine triphosphate brain-derived neurotrophic factor bradykinin cyclic adenosine monophosphate cyclic guanosine monophosphate voltage-gated calcium channels 2,3-cyclic nucleotide-3-phosphodiesterase central nervous system cyclooxygenase cerebrospinal fluid diacylglycerol equilibrium potential for K+, Na+, Ca2+ and Cl-respectively excitatory amino acid transporter electron microscopy endothelin

7-aminobutiric acid guanilate cyclase glial acidic fibrillary protein human immunodeficiency virus inositol (1,4,5) trisphosphate inositol (1,4,5) trisphosphate receptor inwardly rectifying K+ channels





kainate nicotinic acid adenine dinucleotide phosphate voltage-gated sodium channels sodium-calcium exchanger nerve growth factor N-methyl-D-aspartate oligodendrocyte precursor cells platelet-activating factor phospholipase C proteolipid protein plasmalemmal calcium ATPase peripheral nervous system ryanodine receptor sarco(endo)plasmic reticulum calcium ATPase membrane potential intracellular free calcium concentration extracellular concentrations of potassium, sodium, calcium and chloride respectively intracellular concentrations of potassium, sodium, calcium and chloride respectively o


Physiology of Glia

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