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 The
Neuronal
Environment
Brain Homeostasis
in Health and Disease
Edited by
Wolfgang Walz

Humana Press
The Neuronal Environment
 Contemporary Neuroscience

The Neuronal Environment: Brain Highly Selective Neurotoxins: Basic and

Homeostasis in Health and Disease, Clinical Applications, edited by
edited by Wolfgang Walz, 2002 Richard M. Kostrzewa, 1998
Neurotransmitter Transporters: Neuroinflammation: Mechanisms and
Structure, Function, and Regulation, Management, edited by Paul L.
2/e, edited by Maarten E. A. Reith, Wood, 1998
2002 Neuroprotective Signal Transduction,
Pathogenesis of Neurodegenerative edited by Mark P. Mattson, 1998
Disorders, edited by Mark P. Mattson, Clinical Pharmacology of Cerebral
2001 Ischemia, edited by Gert J. Ter Horst
Stem Cells and CNS Development, edited and Jakob Korf, 1997
by Mahendra S. Rao, 2001 Molecular Mechanisms of Dementia,
Neurobiology of Spinal Cord Injury, edited by Wilma Wasco and
edited by Robert G. Kalb and Rudolph E. Tanzi, 1997
Stephen M. Strittmatter, 2000 Neurotransmitter Transporters:
Cerebral Signal Transduction: From Structure, Function, and Regulation,
First to Fourth Messengers, edited by edited by Maarten E. A. Reith, 1997
Maarten E. A. Reith, 2000 Motor Activity and Movement Disorders:
Central Nervous System Diseases: Research Issues and Applications,
Innovative Animal Models from Lab to edited by Paul R. Sanberg,
Clinic, edited by Dwaine F. Emerich, Klaus-Peter Ossenkopp, and
Reginald L. Dean, III, Martin Kavaliers, 1996
and Paul R. Sanberg, 2000 Neurotherapeutics: Emerging
Mitochondrial Inhibitors and Strategies, edited by Linda M. Pullan
Neurodegenerative Disorders, edited and Jitendra Patel, 1996
by Paul R. Sanberg, Hitoo Nishino, Neuron–Glia Interrelations During
and Cesario V. Borlongan, 2000 Phylogeny: II. Plasticity and
Cerebral Ischemia: Molecular and Regeneration, edited by Antonia
Cellular Pathophysiology, edited by Vernadakis and Betty I. Roots, 1995
Wolfgang Walz, 1999 Neuron–Glia Interrelations During
Cell Transplantation for Neurological Phylogeny: I. Phylogeny and
Disorders, edited by Ontogeny of Glial Cells, edited by
Thomas B. Freeman and Antonia Vernadakis and
Håkan Widner,1998 Betty I. Roots, 1995
Gene Therapy for Neurological The Biology of Neuropeptide Y and
Disorders and Brain Tumors, edited Related Peptides, edited
by E. Antonio Chiocca and by William F. Colmers and
Xandra O. Breakefield, 1998 Claes Wahlestedt, 1993
 The Neuronal
Environment
Brain Homeostasis
in Health and Disease

Edited by

Wolfgang Walz
Department of Physiology,
University of Saskatchewan, Saskatoon,
Saskatchawan, Canada

Humana Press Totowa, New Jersey

© 2002 Humana Press Inc.
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Serotonin, and Neuropeptide Systems,” Further Evidence for Volume Transmission, by A. Jensson, L. Descarries,
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The neuronal environment: brain homeostasis in health and diease/edited by

Wolfgang Walz
p. cm.--(Contemporary neuroscience)
Includes bibliographical references and index.
ISBN : 0-89603-882-3 (alk. paper)
1. Neurons--Physiology. 2. Homeostasis. 3. Neuroglia. 4. Brain--Metabolism. 5. Blood-brain barrier.
I. Walz, Wolfgang. II. Series.

QP363.N47758 2002
612.8’2--dc21
2001039827
 Preface

To function properly, neurons cannot tolerate fluctuations of their local environ-

mental variables. This mainly results from their high degree of specialization in synap-
tic integration and action potential conduction. Even small changes of certain
extracellular ion concentrations, as well as in the dimensions of the extracellular space,
alter ion channel kinetics in such a way as to distort the information represented by the
nerve impulses. Another potential problem is the huge consumption of glucose and
oxygen by neurons caused by the heavy compensatory ion pumping used for counter-
acting passive ion flux. This problem is compounded by the low glucose storage capac-
ity of the neurons. A complicated structure surrounds the neurons to sustain the required
level of metabolites and to remove waste products.
The Neuronal Environment: Brain Homeostasis in Health and Disease
examines the function of all the components involved, including their perturbation dur-
ing major disease states, and relates them to neuronal demands. The two introductory
chapters focus on neuronal requirements. The dependence of their excitability on
external factors that accumulate in the extracellular space, as well as their varying
demands for energy metabolites, are described. Following that, the close interaction of
neurons with elements of their microenvironment is illustrated. The extracellular space
is no longer seen as a passive constituent of the CNS, but as a separate compartment in
its own right, as a communication channel, and an entity that reacts with plastic changes
in its size that will affect the concentrations of all its contents. Astrocytes participate in
many neuronal processes, particularly in the removal of excess waste and signal sub-
stances, the supply of energy metabolites, and the modulation of synaptic transmission.
In addition to their homeostatic role, astrocytes are now seen as an active partner
involved in synaptic transmission between neurons. The classical example of a close
relationship of neurons with a component of their environment is, of course, their rela-
tionship with the surrounding myelin sheath. This speeds up action potential conduc-
tion, but is itself a potential source of problems in various disease states. In the last few
years new imaging techniques have demonstrated a close coupling between local blood
flow and neuronal activity, and several theories have been put forward to explain these
interactions. The special status of the brain in having its own insulated circulation
system — the cerebrospinal fluid contained in the ventricles and ducts — is also under-
lined. The brain is the only organ that is protected from fluctuations of blood-borne
chemicals by the existence of the blood–brain barrier. However, windows exist in this
barrier in the form of the circumventricular organs that allow direct two-way commu-
nication between neurons and blood constituents. Finally, despite their protection and
insulation, the neurons are accessible to the immune system. Resident macrophages
and invasion by blood-borne immune cells that cross the endothelial cell barrier enable

v
vi Preface

an immune reaction to take place. This complex interaction of neurons with their
immediate environment is integral to the tasks that the neurons must perform to ensure
that the organism can cope with its environmental challenges. Most diseases originat-
ing in the brain start in these accessory systems of the neuronal microenvironment and
affect neurons only second hand. Therefore, understanding the elements of the neu-
ronal environment and the interactions with neurons, and with each other, is crucial in
understanding the development and impact of most brain diseases.
All the authors contributing to The Neuronal Environment: Brain Homeostasis in
Health and Disease have made an attempt not only to explain the normal functioning
of these accessory elements, but also their involvement in major diseases. Therefore,
this book not only addresses researchers, graduate students, and educators who want to
understand the complex environment of neurons, but also health professionals who
need to know more about the normal homeostatic role of the neuronal environment to
follow disease patterns.
Wolfgang Walz
 Contents

Preface .............................................................................................................. v
Contributors ................................................................................................... ix
I. NEURONAL ACTIVITY AND ITS DEPENDENCE ON THE MICROENVIRONMENT
1 Central Nervous System Microenvironment
and Neuronal Excitability ....................................................................... 3
Stephen Dombrowski, Imad Najm, and Damir Janigro
2 Neuronal Energy Requirements .............................................................. 25
Avital Schurr
II. BRAIN MICROENVIRONMENT
3 Plasticity of the Extracellular Space ........................................................ 57
Eva Syková
4 Transmitter–Receptor Mismatches in Central Dopamine,
Serotonin, and Neuropeptide Systems: Further Evidence
for Volume Transmission ........................................................................ 83
Anders Jansson, Laurent Descarries, Virginia Cornea-Hébert,
Mustapha Riad, Daniel Vergé, Mircea Bancila,
Luigi Francesco Agnati, and Kjell Fuxe
5 The Extracellular Matrix in Neural Development, Plasticity,
and Regeneration.................................................................................. 109
Jeremy Garwood, Nicolas Heck, Franck Rigato,
and Andreas Faissner
6 Homeostatic Properties of Astrocytes .................................................. 159
Wolfgang Walz and Bernhard H. J. Juurlink
7 Glutamate–Mediated Astrocyte–Neuron Communication
in Brain Physiology and Pathology .................................................. 187
Micaela Zonta and Giorgio Carmignoto
8 Axonal Conduction and Myelin ............................................................ 211
Jeffrey D. Kocsis
9 Coupling of Blood Flow to Neuronal Excitability .............................. 233
Albert Gjedde
III. BRAIN MACROENVIRONMENT
10 Choroid Plexus and the Cerebrospinal–Interstitial
Fluid System .......................................................................................... 261
Roy O. Weller
vii
viii Contents

11 The Blood–Brain Barrier .......................................................................... 277

Richard F. Keep
12 Circumventricular Organs ...................................................................... 309
James W. Anderson and Alastair V. Ferguson
13 Glial Linings of the Brain ........................................................................ 341
Marc R. Del Bigio
IV. IMMUNE SYSTEM-NEURON INTERACTIONS
14 Microglia in the CNS .............................................................................. 379
Sophie Chabot and V. Wee Yong
15 Invasion of Ischemic Brain by Immune Cells ...................................... 401
Hiroyuki Kato and Takanori Oikawa
Index.............................................................................................................. 419
 Contributors

LUIGI FRANCESCO AGNATI, Department of Human Physiology,

University of Modena, Modena, Italy
JAMES W. ANDERSON, Department of Physiology, Queen’s University,
Kingston, Ontario, Canada
MIRCEA BANCILA, Laboratoire de Neurobiologie de Signaux Intercellulaires,
Institut des Neurosciences, Université Pierre et Marie Curie, Paris, France
GIORGIO CARMIGNOTO, Department of Experimental Biomedical Sciences,
University of Padova, Padova, Italy
SOPHIE CHABOT, Department of Oncology and Clinical Neurosciences,
University of Calgary, Calgary, Canada
VIRGINIA CORNEA-HÉBERT, Département de Pathologie et Biologie Cellulaire,
Université de Montréal, Montréal, Canada
MARC DEL BIGIO, Department of Pathology, Health Sciences Centre and
University of Manitoba, Winnipeg, Canada
LAURENT DESCARRIES, Département de Pathologie et Biologie Cellulaire,
Université de Montréal, Montréal, Canada
STEPHEN DOMBROWSKI, Department of Neurosurgery,
Cleveland Clinic Foundation, Cleveland, OH
ANDREAS FAISSNER, Laboratoire de Neurobiologie du Developpment et de la
Regeneration, Strasbourg, France
ALASTAIR V. FERGUSON, Department of Physiology, Queen's University,
Kingston, Ontario, Canada
KJELL FUXE, Department of Neuroscience, Karolinska Institute, Stockholm, Sweden
JEREMY GARWOOD, Laboratoire de Neurobiologie du Developpment et de la
Regeneration, Strasbourg, France
ALBERT GJEDDE, The Pathophysiology and Experimental Tomography Center,
Aarhus General Hospital, Aarhus C, Denmark
NICOLAS HECK, Centre National De la Recherche Scientifique, Strasbourg, France
DAMIR JANIGRO, Division of Cerebrovascular Research,
Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, OH
ANDERS JANSSON, Department of Neuroscience, Division of Cellular
and Molecular Neurochemistry, Karolinska Institute, Stockholm, Sweden

ix
x Contributors

BERNHARD H.J. JUURLINK, Department of Anatomy and Cell Biology,

University Saskatchewan, Saskatoon, Canada
HIROYUKI KATO, Department of Neurology and Neuroendovascular Therapy,
Tohoku University School of Medicine, Sendai, Japan
RICHARD F. KEEP, Departments of Surgery and Physiology,
University of Michigan, Ann Arbor, MI
JEFFERY D. KOCSIS, Neuroscience Research Center, Department of Veterans Affairs
Medical Center, Yale University School of Medicine, West Haven, CT
IMAD NAJM, Department of Neurosurgery, Cleveland Clinic Foundation,
Cleveland, OH
TAKANORI OIKAWA, Department of Neurology, Tohoku University School of
Medicine, Sendai, Japan
MUSTAPHA RIAD, Departement de Pathologie et Biologie Cellulaire,
Universite de Montreal, Montreal, Canada
FRANCK RIGATO, Centre Natioanl De la Recherche Scientifique, Strasbourg, France
AVITAL SCHURR, Department of Anesthesiology, University of Louisville,
School of Medicine, Louisville, KY
EVA SYKOVÁ, Department of Neuroscience, Institute of Experimental Medicine,
Academy of Sciences, Prague, Czech Republic
DANIEL VERGÉ, Laboratoire de Neurobiologie de Signaux Intercellulaires,
Institut des Neurosciences, Université Pierre et Marie Curie, Paris, France
WOLFGANG WALZ, Department of Physiology, University of Saskatchewan,
Saskatoon, Canada
ROY O. WELLER, Department of Microbiology and Pathology,
Southhampton General Hospital, Southampton, UK
V. WEE YONG, Departments of Oncology and Clinical Neurosciences,
University of Calgary, Calgary, Canada
MICAELA ZONTA, Department of Experimental Biomedical Sciences,
University of Padova, Padova, Italy
CNS Microenvironment and Excitability 1

I
NEURONAL ACTIVITY AND ITS DEPENDENCE
ON THE MICROENVIRONMENT
CNS Microenvironment and Excitability 3

1
Central Nervous System Microenvironment
and Neuronal Excitability

Stephen Dombrowski, Imad Najm, and Damir Janigro

1. INTRODUCTION
The biological cell membrane, the interface between the cell and its environment, is
a complex biochemical entity, one of whose major jobs is to allow or impede transport
of specific substances in one direction or another. A related major job of the cell mem-
brane is the maintenance of chemical gradients, particularly electrochemical gradients,
across the plasma membrane. These gradients can be of high specificity (e.g., sodium
vs. potassium ions), and of great functional significance (e.g., in the production of
action potentials in nerve and muscle cells) (1).
The separation of intra- and extracellular compartments by lipidic bilayers is one of
the crucial steps in evolution. One of the consequences of this partition is the signifi-
cant difference in the cytosol and extracellular contents of cells. Furthermore, cells
with different functions tend to have different intracellular composition, and cellular
elements from different tissues are exposed to extracellular media of different chemi-
cal nature. In addition to a variety of nutrients and growth factors, the extracellular
milieu also contains molecules that either promote cell differentiation (e.g., adhesion
molecules) or survival (growth factors), as well as ions constituting the basis of electri-
cal activity (or silence) of mammalian cells. Granting that appropriate control of the
composition of the extracellular space significantly impacts the cytosolic content, and
vice versa, change in the intracellular components of central nervous system (CNS)
cells impacts the composition of extracellular fluids. The dynamic process involved in
the maintenance of the composition of intra- and extracellular ingredients is called
“homeostasis.”
The general design used for the separation of intracellular and extracellular space
has also been used during the evolution to maintain the nervous system of vertebrates,
isolated, at least in part, from systemic influences. Therefore, a double bilayer, similar
to the lipophilic barrier isolating the cytoplasm from the external milieu and formed by
brain microvascular endothelial cells [the blood–brain barrier (BBB)], separates the
CNS from the blood, in vertebrates.
From a neuroscientist’s point of view, the fact that the neuronal extracellular milieu
composition is controlled by such a complex cascade of serially occurring events best
illustrates the relevance of controlled neuronal activity to ensure the organism’s
From: The Neuronal Environment: Brain Homeostasis in Health and Disease
Edited by: W. Walz © Humana Press Inc., Totowa, NJ

3
 4
Table 1
Examples of Homeostatic Mechanisms in CNS and Their Possible Involvement in Pathogenesis
Mechanisms involved Cell types involved Pathology Refs.
Barrier function BBB Endothelium Brain tumors
Choroid plexus Neuroepithelium Stroke
Brain–CSF barrier Pia–glia Hypertension (90)
Alzheimer’s (91)
P-glycoprotein Endothelium Epilepsy
Transport of nutrients Glucose transport Endothelium GLUT1 deficiency
and neurotransmitters GLUT1–GLUT3 Astrocytes Epilepsy
4

Alzheimer’s
Amino acid transport Neurons (92–96)
Glia (43,45,46,97,98)
GLAST Endothelium

Dombrowski, Najm, and Janigro

Ion homeostasis Na+/K+-ATPase Neurons Epilepsy
Glia Vascular dementia
Endothelium
Inward rectifier Astrocytes
Metabolic control Autoregulation Vascular smooth muscle; Head injury (99,100)
of CNS function Systemic influences glia, neurons
CNS Microenvironment and Excitability 5

survival (Table 1). The following paragraphs summarize some of the most relevant
mechanisms involved in the regulation of neuronal excitability by factors present in the
extracellular milieu.

2. CELLULAR CORRELATES OF BRAIN HOMEOSTASIS

2.1. Neuroglia
The necessity for tight control of the composition of brain extracellular fluids is in
part a consequence of the evolutionary push for miniaturization of the cellular compo-
nents of the CNS (neurons and glia), paralleled by the need to produce ultrafast signal-
ing at the neuronal synapse, and to allow comparably fast neural transmissions along
axons. Functional compromise between a high velocity of neuronal computation and
reduced size of the neuron-to-neuron axonal wiring has been reached, in vertebrates,
by ensheathing the axons by a myelin isolator produced by oligodendroglia, allowing
for so-called “saltatory conductance” (2). One of the clear advantages of this design is
that the myelin sheath occupies much less volume than an equally conductive axon
with a much larger diameter would occupy (for mathematical modeling and other bio-
physical considerations, see ref. 3).
Miniaturization of the vertebrate CNS occurred as a consequence of the necessity to
protect the brain and spinal cord with a bony structure, limiting the overall volume
available for cellular expansion. A consequence of this limiting factor is that the extra-
cellular space in the brain is very small, amplifying the concentration changes occur-
ring across the plasmalemma surrounding the cells (4). The size of the extracellular
space is not homogeneous, and regional differences have been found, even within the
contiguous CA1 and CA3 hippocampal regions (5). The possibility that these regional
variations also relate to different glial subpopulations within the hippocampus has been
proposed (6).
Finally, in an attempt to further minimize the cellular number and volume of the
CNS, the lymphatic drainage apparatus has been sacrificed, leaving the composition of
extracellular fluids in the brain at the mercy of the brain cells themselves. The subse-
quent necessity to shield the central nervous system from uncontrolled systemic influ-
ences, and in order to minimize the extravasation of potentially noxious or osmotically
active molecules from the blood, is perhaps the best-understood reason for the creation
of the blood–brain-barrier (7–9). Similarly, the requirement for an extralymphatic
mechanism of clearance and homeostasis constitutes the teleonomic reason for the
numeric preponderance of glial cells in the mammalian central nervous system. These
glia are directly responsible for the control of the composition of the extracellular space.
Glial cells themselves do not constitute a homogeneous population, and at least three
classes of glial cells have been described. Oligodendroglia are primarily responsible
for the production of myelin, which isolates axons, leaving unsheathed segments with
high densities of sodium and potassium channels (10,11). Astrocytes are present in
both gray and white matter of the CNS, and are perhaps the most numerous subpopula-
tion of glial cells. Astrocytes are involved in a number of different processes, including
the control of ionic homeostasis, control of neuronal metabolism, as well as mainte-
nance of blood–brain barrier integrity (12–19); recent evidence also suggests that they
may actively participate in synaptic transmission (20–23). Microglia are the cellular
6 Dombrowski, Najm, and Janigro

substrates of the neuroimmune response. Their possible role in the homeostasis of CNS
extracellular fluids is not known, but these cells express ion channels involved in the
control of potassium homeostasis performed by astrocytes (24,25).
2.2. Vascular Endothelium and Smooth Muscle
In addition to parenchymally located glial cells, at least two additional cell types
participate in the process of the control of the composition of the extracellular space in
the brain: the cellular elements constituting intraparenchymal vessels, the endothelial
cells lining the intraluminal portion of blood vessels, and only cellular element consti-
tuting the BBB at the capillary level; and vascular smooth muscle, the final effectors
responsible for the control of cerebral perfusion.
There are numerous ways by which these vascular elements may cooperate with
parenchymal glia toward the maintenance of a stable extracellular milieu. BBB endo-
thelial cells are believed to control ionic homeostasis, by preventing equalization of
plasma levels of ions with those present in the cerebral spinal fluid (26–28). Part of this
process is energy-dependent, and directly impacts the ionic homeostasis for potassium
ions (see Subheading 3.).
Vascular smooth muscle are also indirectly involved in the control of brain homeo-
stasis, since their powerful effect on the control of cerebral perfusion will be the final
determinant of the amount of oxygen and glucose delivered to the brain, as well as to
the level of “cleansing” by cerebral blood flow of potential noxious metabolites pro-
duced by neural activity. The control of cerebral circulation is mostly independent of
extrinsic neuronal influences (29). Both capillary function and the amount of blood
perfusing the brain parenchyma are directly proportional to the metabolic activity of
neuronal cells, a phenomenon called “autoregulation,” which appears to depend on a
number of different mechanisms, including nitric oxide, adenosine, potassium, and pH
(30–35).
Finally, vascular (endothelial cells and vascular smooth muscle) and parenchymal
(neurons and glia) cells cooperate closely, and directly influence each other’s develop-
ment. The best-understood mechanism of this tight cell-to-cell interaction is perhaps
the ontogenesis of the blood–brain barrier, a phenomenon directly dependent on the
presence of abluminal glial endfeet, which transmit as-yet unknown signals to neigh-
boring endothelial cells (17,36,37). This example clearly illustrates one of the unique
mechanisms by which the central nervous system parenchyma influences the cerebral
vasculature, without involvement of signals generated distally, a feature that is com-
mon in the systemic circulation, where barrier function is not crucial, because of the
presence of lymphatic drainage. Note that this general difference does not apply to
highly specialized peripheral systems, such as the testicle, where active barrier func-
tion is bestowed upon capillary endothelial cells (38).

3. BASIC ELECTROPHYSIOLOGY
AS RELEVANT TO EXTRACELLULAR SPACE (ECS) HOMEOSTASIS
Electrical phenomena occur whenever charges of opposite sign are separated or
moved in a given direction. Static electricity is the accumulation of electric charge:
An electric current results when these charges flow across a permissive material, called
a “conductor.” An ion current is a particular type of current carried by charges present
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