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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
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Clinic, edited by Dwaine F. Emerich, Klaus-Peter Ossenkopp, and
Reginald L. Dean, III, Martin Kavaliers, 1996
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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
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Gene Therapy for Neurological The Biology of Neuropeptide Y and
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The Neuronal
Environment
Brain Homeostasis
in Health and Disease
Edited by
Wolfgang Walz
Department of Physiology,
University of Saskatchewan, Saskatoon,
Saskatchawan, Canada
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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
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
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
on atoms or small molecules flowing in aqueous solution. Separation of charges in an

aqueous solution can be achieved by inserting an impermeable membrane in the solu-
tion itself. In mammalian cells, these membranes coincide with the plasma membrane,
and its lipophylic composition ensures a remarkable level of electrical isolation for
cells and tissues. Excitable cells, as well as most nonexcitable cells, are characterized
by an asymmetric distribution of electrical charges across the plasma membrane.
The control of the distribution of electrical charges across the plasma membrane is an
energy-consuming process. A significant portion of this homeostatic control involves the
tight regulation of sodium and potassium gradients. The molecular mechanism respon-
sible is the so-called “Na+/K+-adenosine triphosphatase (ATPase),” an ubiquitous enzyme
whose activity is highly dependent on intra-cellular levels of ATP. It is clear that even
minimal changes in the availability of energy substrates (ATP) will cause significant
changes in the resting potential of the cells. It is well understood that intracellular Na+
concentrations are controlled by the exchange of three Na+ against two K+, an electro-
genic mechanism that contributes substantially to the regulation of resting membrane
potential (RMP) in both neurons and glia. The activity of this enzyme depends, in addi-
tion to availability of ATP, on internal Na+ and external K+ concentrations, and, since
[K+] (and, to a lesser extent, [Na+]) are the main ionic mechanism of the generation of a
stable resting membrane potential (39), it becomes obvious that energy supply, ionic
homeostasis, and the control of RMP are closely interconnected mechanisms. Because
the probability of neuronal firing depends to a large extent on the transmembrane volt-
age, the link between ionic homeostasis and neuronal excitability becomes evident.
Neuronal cells use a single type of long distance signaling strategy, based on the
propagation of all-or-nothing action potentials. Sodium action potentials, such as those
recorded in axons or cell bodies, are relatively invariant in normal tissue, and thus the
shape and duration of these electrical signals does not vary significantly within the
nervous system. Calcium action potentials are similarly predictable, but the underlying
ionic mechanism can be complex, depending on the cell type, and on the topographic
location within the cell. The terms “sodium action potential” and “calcium action
potential” refer to the initial (depolarizing) phase of these rapid membrane polarity
changes, and, although genetic or molecular alteration of INa and ICa can significantly
affect neuronal firing and, ultimately, CNS/peripheral nervous system neurophysiol-
ogy, gross changes in neuronal excitability may also result by altering the repolariza-
tion phase of individual action potentials because of the dramatic changes in
extracellular potassium concentrations that accompany neuronal firing, and the con-
secutive feedback effect of [K+]out on neuronal resting membrane potential (Fig. 1).
From a functional standpoint, the genesis of fast, sodium action potentials is a hall-
mark of neuronal function, to the degree that during neurophysiological recordings,
presence or absence of Na+ spikes is frequently used to determine the neuronal or glial
cell type (40–42). Recently, this notion has been challenged, and glial action potentials
have been reported with increasing frequency (43–46). These responses, however, usu-
ally appear to be associated with pathologic conditions (brain tumors, epilepsy), and
the old perception that neuronal cells are the exclusive tenants of sufficient INa density,
to promote active responses, is still generally accepted.
Although it is obvious that any significant ionic flux across neuronal membranes
will invariably lead to changes in the extracellular/intercellular milieu composition,
Fig. 1. Diagrammatic representations of potassium fluxes into the CNS. This scheme is
based on original spatial buffering concepts described by Orkand (46a), as well as from results
inferred from experiments on isolated cells and BVs isolated from the brain (30). The depo-
larization of pre- and postsynaptic terminals depicted in the right side of the picture causes
opening of voltage-dependent potassium channels in neurons. Activation of outward potas-
sium currents causes large potassium fluxes from the cytoplasm to the ECS. Although a frac-
tion of excess potassium ions may directly return into the neuronal cell by active transport
via Na +/K +-ATPase (not shown in figure), additional uptake of potassium occurs, under most
conditions, by voltage-dependent uptake into astrocytic endfeet. Fluxes of potassium through
the glial syncytium may then lead either to return of K+ into the ECS surrounding the neurons,
or, perhaps, under more extreme conditions, to release of excess potassium into the blood stream
by glial endfeet. The top part of the figure represents the passage of potassium across one single
astrocyte, characterized by a cell body and endfeet surrounding a BV, as well as an
ensheathment of synaptic terminals. The bottom part of the figure refers to a more common
situation, in which multiple glial cells are coupled by gap junctions (6). Gap junction expres-
sion is altered in epileptic tissue (45).
the following subheading describes in some detail only mechanisms involved in the
control of K+ homeostasis, because K+ ions have historically been linked to strict con-
trol of neuronal excitation by their profound effect on neuronal resting potential and
synaptic transmission. Recent evidence from the author’s laboratory also suggests that
failure of K+ homeostasis by glial cells may lead to abnormal extracellular fluid com-
position and a propensity to seizures.
4. POTASSIUM HOMEOSTASIS
Potassium channels are present in virtually every animal cell type, and serve a vari-
ety of functions. Historically, these ubiquitous ionic mechanisms were associated with
control of cell resting potential and, after the discovery of sodium action potentials, the
repolarization phase leading to the recovery of pre-action potential RMPs. Potassium
channels belong to a large and complex group that can be divided into functional, struc-
tural, or molecular families. Voltage-dependent K channels (KV) are constituted of
six transmembrane regions (S1–S6) and a P or H5 segment between S5 and S6; the selec-
tivity filter contains a specific sequence (glycine-tyrosine-glycine); the voltage sensor
consists of positively charged amino acids in the S4 region. Inward rectifier potassium
channels (KIR) are distantly related to the voltage-dependent family, and are made of
four subunits, each consisting of two transmembrane segments (M1 and M2) and a P or
H5 segment located between. These channels do not allow passage of current at posi-
tive potentials. The voltage-dependency of the KV channels depends on the presence of
a voltage sensor, but inward rectification is achieved by voltage-dependent blockade
of the intracellular portion of the channel pore by cytosolic cations (47,48). Opening of
the channels may be achieved by G protein-coupled mechanisms (as in the GIRK sub-
family), or by metabolic changes (intracellular ATP, KIR 6.1, or ATP-sensitive potas-
sium channels) (49–51).
4.1. Extracellular Space Composition
and Regulation of Neuronal Excitability
Central nervous system astrocytes are strategically located in proximity to excitable
neurons, and are sensitive to changes in extracellular ion composition that follow neu-
ronal activity (see diagram in Fig. 1). Several lines of evidence suggest that brain glial
cells support the homeostatic regulation of the neuronal microenvironment. In cortical
regions, glial cells participate in the genesis of the extracellular field potential changes
associated with neuronal depolarization and efflux of potassium in the extracellular
space (52–54).
Several mechanisms have been proposed to explain how astrocytes sense and react
to changes in extracellular potassium concentrations, following both normal and
abnormal neuronal activity. As summarized in the previous paragraphs, neuronal
excitability is regulated by a complex interaction of voltage-dependent ion currents
and synaptically mediated excitatory and inhibitory potentials. In principal neocortical
or hippocampal neurons, depolarizing ion conductances involved in action potential
generation, are regulated primarily by the voltage-dependent activation/inactivation
properties of Na+ and Ca2+ channels; inward Na+ and Ca2+ fluxes also underlie the
generation of excitatory postsynaptic potential (EPSPs). Termination of these depolar-
izing potentials occurs by the voltage- and calcium-dependent activity of intrinsic
potassium conductances, and by activation of interneurons, which release inhibitory
neurotransmitters to produce inhibitory postsynaptic potentials (IPSPs): The latter are
mediated by postsynaptic activation of chloride and potassium currents.
Although INa, ICa, and IEPSP are, under physiological conditions, independent of
modest changes in the driving force for the permeant ions (since ENa and ECa are remote
with respect to cell resting potential), both repolarizing potassium and IPSP conductances
are critically affected by even modest changes in cell RMP, [K+]out and [Cl]in/[Cl]out.
Thus, ionic changes directly associated with excitatory (depolarizing) activity seem to
impact minimally ionic homeostasis, but repolarization and inhibition are powerful
modulators of [K+]out, [Cl–]in/out, and so on. As a consequence, failure to control potas-
sium and chloride homeostasis is likely to promote neuronal excitability by decreasing

the efficacy of repolarizing K currents and IPSPs.
The concentration of potassium in the ECS (KECS), in the mammalian CNS, increases
measurably (from 3 to ~4 mM) during physiological stimulation; to a larger extent (up
to 12 mM), during seizures or direct, synchronous stimulation of afferent pathways;
and to exceedingly high values (>30 mM), during anoxia or spreading depression
(6,41,55,56). Despite these rapid and large changes in KECS, K+ values return to normal
levels in a short period of time. Several mechanisms have been proposed to explain the
rapid clearance of K+ from the ECS, including uptake by glia, passive diffusion, and
neuronal reuptake. Experiments have suggested that glial uptake plays a pivotal role
under conditions in which there is massive Kout accumulation (41,53,55,57). [K]out can
also be redistributed through active removal by blood flow, or by passive diffusion
through the ECS (58); however, these mechanisms alone are not fast enough to account
for the rapid K+ removal from the ECS seen under experimental conditions.
4.2. Astrocytes and Buffering of ECS Potassium
Glial involvement in CNS potassium homeostasis has been long suspected, but never
unequivocally demonstrated in the mammalian CNS. Two different hypotheses have
been formulated: K+ may accumulate directly into astrocytes, and increased local con-
centrations of KECS may be buffered through glial cells by current-carried transport
mechanisms. The combination of potassium uptake into glial cells, immediately fol-
lowed by redistribution through electronically coupled glial gap junctions (“spatial
buffering” [59–65]) provides a valid working hypothesis to explain some of the fea-
tures of K+ movements in the extracellular space. The spatial buffering mechanism
rests on the following hypotheses: Glial RMP closely follows EK (i.e., glial cells are
selectively and exclusively permeant to K+); and glial cells form a topographically
complex syncytium, by virtue of their tight electrotonic coupling via gap junctions.
Both of these hypotheses have been experimentally challenged. A clear correlation
between astrocyte RMP and [K+]out has been described in virtually every glial cell type
studied, but RMP more positive than those predicted by a Nernstian behavior have
been frequently reported (for discussion, see ref. 65). The deviation of glial RMP from
those predicted by Nernstian behavior has been attributed to one or more of the follow-
ing: the electrogenicity of the Na+/K+-ATPase pump; a persistent sodium conductance
activated at cell resting potential (66); chloride currents.
A modification of spatial buffering has been described for retinal Müller cells
(potassium siphoning) (67). This process is characterized by a topographic segregation
of high conductance zones in the plasma membrane. Thus, a large density of potassium
channels is localized in the cell region where extracellular space accumulation occurs,
and distally, at the glial endfeet, where potassium excretion into the ECS occurs.
No significant K fluxes are possible in the central region of the cell, where no K+
removal or excretion occurs. A similar mechanism could explain several features of
extracellular potassium dynamics in cortical structures, and preliminary evidence (65),
supporting a preferential distribution of potassium channels in cortical astrocyte mem-
brane has been recently provided; double recordings from neighboring astrocytes dem-
onstrated that a heterogeneous expression of inward rectifier and outward rectifier
channels is present in these cells. The proposed model of potassium movements in
these syncytia of neocortical astrocytes shared characteristics of both spatial buffering

(influx of potassium driven by Em and EK) and siphoning (segregated expression of
inward rectifier and outward rectifier channels).
4.3. Astrocytic Ion Currents and Potassium Homeostasis

For the purpose of this minireview, we will describe in some detail the endowment
of potassium channels expressed by glial cells in the CNS. Their role in the control of
extracellular K homeostasis is also briefly summarized.
Glial cells express a variety of potassium currents, but the expression of these cur-
rents seems to depend on the glial cell type considered (microglia vs astrocyte vs oligo-
dendroglia), as well as on the experimental conditions used to determine potassium
channel expression. Culturing of glia in vitro dramatically changes the expression of a
variety of glial specific markers, including ion channels. The relevance of these
expression changes is presently unknown. However, since exposure to serum (or, con-
versely, serum deprivation) plays a major role in cell differentiation, it is possible that,
under physiological conditions, the serum-free CNS environment may act as a matura-
tion factor for astrocytic differentiation. When and where brain homeostasis fails, as
the result of opening of the blood–brain barrier, serum proteins will extravasate
into the CNS: This may have profound effects on glial ion channel expression, and
play a major pathogenetic role.
It has been known for a long time that the predominant ion channel mechanism
expressed in astrocytes is the so-called “inward rectifier potassium channel.” The prop-
erties of these channels are consistent with the mechanisms involved in the simul-
taneous control of RMP and voltage-dependent uptake of potassium from the
extracellular space. The coupling of these channels to this dual control mechanism
justifies, in part, the old spatial-buffering theory proposed many years ago by Orkand
(1986). The mechanism of potassium entry into the cell is consistent with the biophysi-
cal properties of inwardly rectifying potassium channels (68,69), but it is still unclear
how the spatial redistribution of potassium ions occurs, and what mechanisms are used
by astrocytes to return potassium ion to the extracellular space. The presence of both
inward and outward currents on astrocytes, if topographically segregated as shown in
retinal astrocytes (67,70), would account for both uptake and redistribution of potas-
sium across cortical structures.
4.3.1. Potassium Uptake via Voltage-Dependent Currents
Glial cells lack regenerative, AP-like responses. However, glial cells express a num-
ber of voltage-, second messenger-, and agonist-operated channels (71–73). Potassium
channels are the most common electrophysiological feature of both cultured and in situ
astrocytes, and can be categorized as follows: channels that allow inward, but not out-
ward, current flow (inward rectifiers [KIR]); channels that allow outward, but not
inward, current flow (delayed rectifier [IDR]; transient outward current [IA]); channels
that are opened by intracellular calcium (I K(Ca) ). Glial potassium channels differ
in their sensitivity to blockers: Inward rectifiers are blocked by submillimolar con-
centrations of external Cs+ and Ba2+; outward IDR and IA are both sensitive to tetraethyl-
ammonium and 4-aminopyridine, but IA blockade by tetraethylammonium requires high
concentrations. Recently, a mixed-cation channel (Iha), permeant to K+ and Na+, has
Fig. 2. Changes in neuronal activity, EC potassium, and glial resting potential, after chemi-
cal ablation of spatial buffering by cesium. The left panel shows the size of EC field potentials
recorded in the CA1 region of the hippocampus during a 1 Hz stimulation trial of 15 min in
duration. The traces below refer to the IC recording, by patch clamp, of glial cell resting poten-
tial during the same period of time, as well as changes in EC potassium. Note that decreased
field potential amplitude does not necessarily correlate with either glial or EC potassium
changes. After exposure of the cells to a saturating concentration of cesium, the EC field poten-
tial response was not significantly altered, suggesting that direct neuronal effects were absent.
However, profound changes in basal concentration of EC potassium (indicated by the milli-
mole values under the bottom traces), as well as glial resting potential, occurred. (Reproduced
with permission from ref. 41.)
been described in cultured astrocytes (74). A cardiac-type outward potassium current

has been described in in situ glia (25); this current (IHERG) seems to be involved in
potassium homeostasis in cooperation with KIR. A direct demonstration that KIR, IHERG,
or Iha play a role in spatial K+ buffering is still lacking, but evidence from both in vivo
and in vitro studies has demonstrated proepileptogenic neuronal changes after applica-
tion of mostly glia-specific potassium channel blockers ([6,25,41]; see also Subhead-
ing 4.3.2., and Figs. 2–6).
Voltage-dependent, tetrodotoxin-sensitive and -insensitive sodium channels are also
expressed in both cultured and in situ glial cells (75). Although astrocytes are inca-
pable of producing action potential-like responses (but see ref. 73), possibly because of
the low Na+ current densities in these cells, a role for Na+ channels in spatial buffering
has been proposed. According to this hypothesis Na+ influx sustains the Na+/K+-ATPase
pump, resulting in net K+ uptake. Finally, calcium channels are represented sparingly
in glial cells, and require either neuronal or otherwise-differentiating factors for
CNS Microenvironment and Excitability
13
Fig. 3. Astrocytes lose inward K+ currents after in vivo traumatic brain injury. Whole-cell voltage-clamped cells in control hippocampal slices
exhibited large Cs+-sensitive currents (A, top and bottom panel), and were characterized by a large Cs+-sensitive component. In contrast, cells in
post-FPI hippocampal slices displayed little Cs+-sensitivity (B, top and bottom panel), and showed a decreased Cs+-sensitive component of the
whole-cell inward currents. (C) The percentage of Cs+-sensitive currents (ICs) for glia in normal and post-FPI hippocampus is shown for membrane
potentials from –140 to –80 mV. Voltage commands consisted of ramps from –170 to +100 mV, over 750 ms, from holding potential of –70 mV.
(Reprinted with permission from ref. 79.)
13
Fig. 4. Neuronal stimulation induces abnormal accumulation of EC K+ and burst discharge

in slices from post-traumatic rats. Field electrode and KSM were placed in CA3 stratum
radiatum. A stimulating electrode was placed in CA2 stratum radiatum. K+ activity recordings
were performed during 0.05- and 1-Hz antidromic stimulation. (A) Control slices (filled circles)
had a basal [K+]out similar to that of bathing a CSF. Antidromic stimulation, at 1 Hz for 4 min,
induced a transient elevation of [K+]out to about 5 mM, and its recovery toward baseline values
within the fourth minute. During the following 0.05 Hz, [K+]out transiently decreased to about
4 mM, then recovered. Post-FPI slices (empty circles) had elevated basal [K+]out during stimu-
lation at 0.05 Hz. When the high-frequency stimulation was performed, [K+]out transiently
increased to 5.4 mM, then decreased to 5 ± 0.05 mM, without reaching the baseline value
(asterisk, p < 0.001). During the following 0.05 Hz, [K+]out transiently decreased to ~4.7 mM.
(B) Post-FPI CA3 develops frequency-dependent afterdischarges for antidromic stimulation.
In control, only a small fraction of slices developed afterdischarges during antidromic 1-Hz
stimulation (28%, 2/7 slices). Post-FPI slices showed a higher excitability. They did not dis-
play afterdischarges during 0.05-Hz stimulation, but afterdischarges appeared during 1-Hz
stimulation (80%, 8/10 slices). (Reprinted with permission from ref. 79.)
expression (71,72); whether ICa can be recorded from in situ hippocampal astrocytes is
still unknown, but release of calcium from intracellular stores, in response to neuro-
transmitters acting on astrocytes, has been clearly demonstrated. Relevant to spatial
buffering, micromolar [Ca2+]i can cause opening of IK(Ca), and may thus participate in
the generation of outward potassium fluxes.
4.3.2. K+ Buffering by Furosemide-Sensitive Na,K,2Cl Cotransporter
Under conditions involving high levels of neuronal activity (e.g., seizures), [K]out
accumulation is accompanied by cell swelling. The swelling that accompanies epilep-
tiform neuronal discharge results from excess activity of ionic mechanisms normally
involved in the control of ECS homeostasis. One of several proposed mechanisms
associated with cell swelling, the Na,K,2Cl co-transporter, is also believed to partici-
pate in uptake of K+ into glia. This transporter is blocked by the general diuretic, furo-
semide. Treatment of epileptic hippocampal slices (treated with bicuculline, 0 Ca2+, or
4-aminopyridine) with furosemide has been shown to inhibit spontaneous burst dis-
charge. It has been hypothesized (76) that this mechanism was related to furosemide
Fig. 5. Abnormal accumulation of EC potassium is caused by impaired glial homeostasis.

In naïve slices, 3-Hz antidromic stimulation induced a modest K rise to 4.9 ± 0.1 mM. At the
end of the 5-min period, [K+]out was 4.5 ± 0.05 mM. In the following 5 min of stimulation at
0.05 Hz, [K+]out reached the value of 3.9 ± 0.1 mM (B). (C) Cs+ (1 mM), added to the control
bath solution, increased baseline [K+]out to 4.9 mM. As expected, blockade of potassium uptake
into glia caused exaggerated potassium transients. These were identical to those recorded from
Cs+-free post-traumatic slices.
blockade of the swelling induced by large ionic (and water) shifts that accompany
Na,K,2Cl co-transporter activity.
4.3.3. K+ Buffering by Na+/K+-ATPase
Neuronal K+ reuptake, and part of the hyperpolarizing undershoot that follows the
action potential is mediated in part by an energy-dependent process that requires
Na+/K+-ATPase activity. Similarly, extracellular potassium accumulation into glia may
depend on energy-dependent processes.
Na+/K+-ATPase activity is regulated by both [Na+]i and [K]out. Thus, extracellular
potassium increases, or Na+ influx will cause activation of this electrogenic uptake
mechanism. As a result, glial cells will accumulate potassium and extrude Na+, the net
result being a hyperpolarization. Whether Na+/K+-ATPase-dependent potassium
uptake plays any role in K buffering is still controversial, partially because selective
pharmacological blockade of the glial pump has been unavailable.
Fig. 6
16
To summarize this brief synopsis on K+ buffering by glia: At least three independent

mechanisms of potassium uptake into astrocytes exist; those mediated by voltage-
dependent ion channel mechanisms are relatively ATP- and energy-independent, but
require a negative RMP (and, thus, indirectly, ATP hydrolysis) and high conductance
to potassium ions; transporters (such as the furosemide-sensitive transporter) are also
energy-independent, but their function results in cellular swelling and subsequent
shrinkage of the extracellular space, a condition known to cause hyperexcitability/syn-
chronization; redistribution of excess [Na]i will eventually require some energy.
Finally, energy-dependent pumps cause electrogenic potassium influx, which, under
normal ionic conditions, leads to hyperpolarization. Under extreme conditions, such as
synchronous neuronal activity during epileptic seizure, and if glial K+ uptake mecha-
nisms are operational one at a time (one K-uptake mechanism per each individual
astrocyte), these mechanisms are likely to fail, as the result of glial depolarization (volt-
age-dependent uptake mechanisms), cell swelling/ECS shrinkage (Na,K,2Cl co-trans-
porter), or energy failure (Na+/K+-ATPase). However, it is known that, even at
exceedingly high [K]out (such as during spreading depression), potassium homeostasis
still occurs; indeed, extracellular potassium levels are quickly returned to physiologi-
cal levels following seemingly overwhelming [K]out increases (>40 mM). It seems rea-
sonable to assume that all these different pathways for K+ uptake exist and cooperate in
maintenance of ionic homeostasis. However, it is still unclear whether these mecha-
nisms are expressed in all astrocytes, or whether segregation of different K-uptake
mechanisms takes place. This question is important, because different brain regions
display different levels of sensitivity to insults, such as head injury, ischemia/anoxia,
and seizures, which cause, or derive from, perturbation of ionic homeostasis.
5. ION HOMEOSTASIS AND NEUROLOGICAL DISEASE

Substantial progress has been made in the understanding of the pathophysiology and
mechanisms involved in the attenuation of brain homeostasis. In many diseases that
Fig. 6. (previous page) Immunocytochemical (ICC) localization of ERG channel protein in

hippocampal astrocytes. Left panel: Electron microscopy of biocytin-filled astrocytes (A and
C) is shown for comparison with ICC of ERG (C1) channel protein in astrocytes (B and D).
Note the similar morphological features of hippocampal astrocytes of biocytin-filled and ERG-
immunopositive cell bodies (A and B) and their processes (arrows, C and D). ERG immuno-
reactivity was confined within the cell body cytoplasm of astrocytes, and within large primary
astrocytic processes, and on small, branched processes within the neuropil. Note that an oligo-
dendrocyte (O) was immunonegative (A). Pyramidal cells did not show ERG immunoreactiv-
ity. Right panel: ICC localization of ERG channel protein in astrocytes surrounding blood
vessels in hippocampal CA1 (A and D); comparison with biocytin-filled cells (B and C).
(A) Low-power magnification of an ERG imunoreactive astrocyte process forming an astro-
cytic endfoot (AE) around a capillary (BV). The endothelial cell (E) of the capillary wall does
not show ERG immunoreactivity. As comparison, the capillary wall from a biocytin-filled
astrocytic endfoot is shown in B. (D) ICC localization of ERG channel protein in astrocytes
surrounding blood vessels in hippocampal CA3 subregion; note the immunonegative basal
lamina (BL). (C) Comparison with the capillary wall of biocytin-filled astrocytes. (E) Specific-
ity of the ERG antibody is demonstrated in a control section following preabsorption of the
primary antibody. (Reprinted with permission from ref. 25.)
affect the brain, the astrocytes and cerebral endothelium play an active part in the dis-
ease process, with ionic homeostasis becoming disrupted, or modified, in such a way
that there is a dramatic increase in tissue osmolarity, followed by increased water con-
tent. Thus, a notable consequence of homeostatic failure is cerebral edema. Brightman
et al. (77), in the 1960s, classified brain edema into two major types: vasogenic, or
“wet” edema; and cellular cytotoxic, or “dry” edema. The extravasation of plasma pro-
teins, resulting from a weakened BBB, causes vasogenic edema. Increased BBB per-
meability may also be the outcome of enhanced pinocytotic activity. Changes in cyclic
nucleotides, arachidonic acid, histamine, and other mediators may contribute to the
local changes in BBB permeability. Once established, vasogenic edema can spread
under the influence of hydrostatic and oncotic pressure. In cytotoxic edema, the pri-
mary target is the intracellular metabolic machinery (i.e., ATP-dependent sodium
pump) and/or metabolic substrates. The mechanisms involved in the generation of
cytotoxic edema may lead to glial swelling, changes in BBB function, and, finally,
production of vasogenic edema.
Cerebral edema is commonly associated with acute episodes of neurological disease
(e.g., head injury), but it is also recognized that less-dramatic increases in CNS water
content may chronically and regionally accompany persistent conditions, such as mul-
tiple sclerosis, Alzheimer’s dementia, and perhaps some forms of epilepsy. Here are
reviewed only a few examples of experimental evidence linking changes in potassium
homeostasis to acute or chronic neurological disease. Table 1 summarizes other
homeostatic mechanisms that may impact transmitters, or other molecules and ions.
5.1. Astrocytes and Epilepsy
Given the considerations earlier in this chapter, it is evident that failure of potassium
homeostasis may become epileptogenic. Whether this concept applies only to experi-
mental reality, or extends to the true etiology of the disease, is unknown. Indirect evi-
dence linking potassium uptake failure to seizures is, however, accumulating.
Potassium channel mechanisms that are believed to be involved in astrocytic function
are altered in conditions such as human epilepsy. Several investigators (43,46,78,79)
have clearly demonstrated deficits of inward rectifier occurrence in reactive astrocytes,
in both human and animal models of epilepsy. These reactive glia were found in animal
models of neuronal injury, as well as in resections from cortical structures from human
epileptic patients affected by epilepsy refractory to drug treatment.
The fact that conditions such as epilepsy are associated with loss of an important
mechanism of potassium homeostasis by astrocytes has led to the hypothesis that per-
haps ablation of voltage-dependent potassium uptake by glia could lead to neuronal
hyperexcitability/synchronization. This has been shown indirectly by two different
models. In the first set of experiments, it has been shown that blockade of extracellular
potassium uptake into hippocampal astrocytes by millimolar concentration of cesium,
causes profound changes in the dynamics of extracellular potassium, as well as impor-
tant changes in neuronal excitability and synchronization. Furthermore, these manipu-
lations had a profound effect on synaptic plasticity, of as-yet unknown significance for
pathological changes (41). Figure 2 shows some of the results of these experiments.
Taken together, these results suggested that chemical ablation of potassium uptake
into glia may be epileptogenic. Numerous issues, however, complicate the interpreta-
tion of these results, such as possible effects of Cs+ on neurons, or on channels other
than KIR (e.g., Iha or Ih [74,80–82]). Further evidence to support the hypothesis that the
effects of acutely applied Cs+ were indeed mediated by glia came from a separate set of
experiments, in which it was shown that traumatic brain injury (TBI), induced in an
animal model, decreases inward rectifier channel expression in glia. These functional
expression changes were comparable to those found in resections from epilepsy
patients, and, quantitatively, here virtually undistinguishable from the effects of cesium
applied in vitro (Figs. 3–5). This is of relevance, since TBI causes propensity toward
unusual hyperexcitability, and may be proepileptogenic (83,84). Thus, these results,
combined with knowledge of the glial changes occurring in human epileptic tissue,
strongly suggested an etiological, and perhaps temporal, link between an initial astro-
cytic deficit, leading to loss of homeostatic control, exaggerated [K+]out transients, and
proepileptogenic changes in neuronal function.
Consistent with the idea that loss of inward rectification/potassium uptake mecha-
nisms, leading to neurological disease, may greatly affect neuronal function is the fact
that potassium transients, as well as changes in neuronal excitability observed in post-
traumatic brains, lacking inward rectification expression in glia, were comparable to
proepileptogenic changes observed in naïve slices treated with cesium. The results of
these experiments are shown in Figs. 4–6.
Finally, it has been recently shown that “channelopaties,” which may be involved
in seizure disorders, affect the expression of ion channels usually associated with
cardiac function (85,86), and responsible for the so-called “long QT syndrome”
(85). Long QT syndrome genes appear to be frequently associated with various
forms of human epilepsy (87–89). In the CNS, the gene product responsible for one
form of long QT is found primarily in glia (Fig. 6); furthermore, blockade of this
current with antiarrhythmic drugs specific for IHERG led to neuronal excitability
changes identical to those obtained after exposure of hippocampal slices to Cs+, or
after TBI in vivo (25).
6. CONCLUSIONS
Neuronal excitability is controlled by a variety of factors, including intrinsic and
extrinsic mechanisms. The fact that the CNS milieu is normally shielded from systemic
influences makes neuronal activity mostly independent of systemic influences. However,
failure of these barrier mechanisms, and/or failure of internal mechanisms of ionic
homeostasis, may lead to chronic neurological diseases, such as epilepsy. Increasing evi-
dence has linked failure of astrocytic function, particularly uptake of potassium, to
epileptic disorders, and experimentally induced defects that are proepileptogenic have
also been found in human epileptic tissue.
ACKNOWLEDGMENTS
The authors’ work reported here was supported by NIH-1R29 HL51614, NIH-
2RO1 HL51614, and NIH-RO1 NS38195. We wish to acknowledge the experimental
and conceptual help of many colleagues during the past several years, including
Drs. P. A. Schwartzkroin, J. Wenzel, R. D’Ambrosio, A. Emmi, G. Maccaferri,
E. Guatteo, S. Grady, and D. Maris.
REFERENCES
1. Hille, B. (1992) in Ion Channels in Excitable Membranes, Sinauer Associates, Sunder-
land, MA.
2. Huxley, A. F. and Stampfli, R. (1949) Evidence for saltatory conductance in peripheral
myelinated nerve. J. Physiol. (Lond.) 108, 315–339.
3. Jack, J. J. B., Noble, D., and Tsien, R. W. (1975) Electric Current Flow in Excitable
Cells, Oxford University Press, New York.
4. Nicholson, C. and Sykova, E. (1998) Extracellular space structure revealed by diffusion
analysis. Trends Neurosci. 21, 207–215.
5. McBain, C. J., Traynelis, S. F., and Dingledine, R. (1990) Regional variations of extra-
cellular space in the hippocampus. Science 249, 674–677.
6. D’Ambrosio, R., Wenzel, J., Schwartzkroin, P. A., and Janigro, D. (1998) Functional spe-
cialization and topographic segregation of hippocampal astrocytes. J. Neurosci. 18, 1–14.
7. Bradbury, M. W. (1993) The blood-brain barrier. Exp. Physiol. 78, 453–472.
8. Davson, H. and Segal, M. B. (1995) The blood-brain barrier, in Physiology of the CSF
and of the Blood-Brain Barrier (Davson, H. and Segal, M. B., eds.), CRC, Boca Raton,
pp. 49–91.
9. Davson, H. and Segal, M. B. (1995) Blood-brain-CSF interactions, in Physiology of the
CSF and Blood-Brain Barrier, CRC, Boca Raton.
10. Suchet, S. (1995) The morphology and ultrastructure of oligodendrocytes and their func-
tional implication, in Neuroglia (Ransom, B. R. and Kettenmann, H., eds.), Oxford Uni-
versity Press, New York, pp. 23–41.
11. Bunge, R. P. and Fernandez-Valle, C. (1995) Basic biology of the Schwann cell, in Neu-
roglia (Ransom, B. R. and Kettenmann, H., eds.), Oxford University Press, New York,
pp. 44–57.
12. Ransom, B. R. and Carlini, W. G. (1986) Electrophysiological properties of astrocytes, in
Astrocytes (Fedoroff, S. and Vernadakis, A., eds.), vol. 2, Academic, Orlando, pp. 1–49.
13. Sontheimer, H. (1992) Astrocytes, as well as neurons, express a diversity of ion channels.
Can. J. Physiol. Pharmacol. 70(Suppl.), S223–238.
14. Bordey, A. and Sontheimer, H. (1997) Postnatal development of ionic currents in rat
hippocampal astrocytes in situ. J. Neurophysiol. 78, 461–477.
15. Chesler, M. and Kraig, R. P. (1989) Intracellular pH transients of mammalian astrocytes.
J. Neuroscience 9, 2011–2019.
16. Forsyth, R. J. (1996) Astrocytes and the delivery of glucose from plasma to neurons.
Neurochem. Int. 28, 231–241.
17. Janzer, R. C. and Raff, M. C. (1987) Astrocytes induce blood-brain barrier properties in
endothelial cells. Nature 325, 253–257.
18. Magistretti, P. J. and Pellerin, L. (1995) Cellular basis of brain energy metabolism and
their relevance to brain imaging-evidence for a prominent role for astrocytes. Cereb. Cor-
tex 5, 301–306.
19. Newman, E. A. (1986) High potassium conductance in astrocyte endfeet. Science 233,
453–454.
20. Pasti, L., Volterra, A., Pozzan, T., and Carmignoto, G. (1997) Intracellular calcium oscil-
lations in astrocytes: a highly plastic, bidirectional form of communication between neu-
rons and astrocytes in situ. J. Neurosci. 17, 7817–7830.
21. Carmignoto, G., Pasti, L., and Pozzan, T. (1998) On the role of voltage-dependent cal-
cium channels in calcium signaling of astrocytes in situ. J. Neurosci. 18, 4637–4645.
22. Araque, A., Parpura, V., Sanzgiri, R. P., and Haydon, P. G. (1999) Tripartite synapses:
glia, the unacknowledged partner. TINS 22, 208–215.
23. Parpura, V., Basarsky, T. A., Liu, F., Jeftinija, K., Jeftinija, S., and Haydon, P. G. (1994)
Glutamate-mediated astrocyte-neuron signaling. Nature 369, 744–747.
24. Zhou, W., Cayabyab, F. S., Pennefather, P. S., Schlichter, L. C., and DeCoursey, T. E.
(1998) HERG-like channels in microglia. J. Gen. Physiol. 111, 781–794.
25. Emmi, A., Wenzel, H. J., Schwartzkroin, P. A., Taglialatela, M., Castaldo, P., Bianchi,
L., et al. (2000) Do glia have heart? Expression and functional role for ether-A-Go-Go
currents in hippocampal astrocytes. J. Neurosci. 20, 3915–3925.
26. Schielke, G. P., Moises, H. C., and Betz, A. L. (1991) Blood to brain sodium transport
and interstitial fluid potassium concentration during early focal ischemia in the rat.
J. Cereb. Blood. Flow. Metab. 11, 466–471.
27. Janigro, D., West, G. A., Gordon, E. L., and Winn, H. R. (1993) ATP-sensitive K+ chan-
nels in rat aorta and brain microvascular endothelial cells. Am. J. Physiol. 265, C812–821.
28. Janigro, D., West, G. A., Nguyen, T.-S., and Winn, H. R. (1994) Regulation of blood-
brain barrier endothelial cells by nitric oxide. Circ. Res. 75, 528–538.
29. Winn, H. R., Dacey, R. G., and Meyberg, M. R. (1989) Cerebral circulation, in Textbook
of Physiology (Patton, F. H. S. S., ed.), WB Saunders, Philadelphia, pp. 952–960.
30. Thien-son, N., Winn, H. R., and Janigro, D. (2000) ATP-sensitive K+ channels may par-
ticipate in the coupling of neuronal activity and cerebrovascular tone. Am. Physiol. Soc.
278, H878–H885.
31. Winn, H. R., Rubio, R., and Berne, R. M. (1981) The role of adenosine in the regulation
of cerebral blood flow. J. Cerebr. Blood Flow Metab. 1, 239–244.
32. Faraci, F. M. and Brian, J. E. J. (1994) Nitric oxide and the cerebral circulation. Stroke
25, 692–703.
33. Iadecola, C. (1993) Regulation of the cerebral microcirculation during neural activity:
is nitric oxide the missing link? Trends Neurosci. 16, 206–214.
34. Ishimaru, S., Okada, Y., Mies, G., and Hossmann, K. A. (1993) Relationship between
blood flow and blood-brain barrier permeability of sodium and albumin in focal ischaemia
of rats: a triple tracer autoradiographic study. Acta Neurochir. Wien 120, 72–80.
35. Kuschinsky, W. (1997) Neuronal-vascular coupling, in Optical Imaging of Brain Func-
tion (Villringer, A. and Dirnagl, U., eds.), Plenum, New York, pp. 167–176.
36. Pekny, M., Stanness, K. A., Eliasson, C., Betsholtz, C., and Janigro, D. (1998) Impaired
induction of blood-brain barrier properties in aortic endothelial cells by astrocytes from
GFAP-deficient mice. Glia 22, 390–400.
37. Penkowa, M., Hidalgo, J., and Moos, T. (1997) Increased astrocytic expression of
metallothioneins I + II in brainstem of adult rats treated with 6-aminonicotinamide. Brain
Res. 774, 256–259.
38. Tsukamoto, H., Hamada, Y., Wu, D., Boado, R. J., and Pardridge, W. M. (1998) GLUT1
glucose transporter: differential gene transcription and mRNA binding to cytosolic and poly-
some proteins in brain and peripheral tissues. Brain Res. Mol. Brain Res. 58, 170–177.
39. Lauger, P. (1991) Na,K-ATPase, in Electrogenic Ion Pumps, Sinauer, Portland, pp. 168–225.
40. Ransom, B. R. and Goldring, S. (1973) Slow hyperpolarization in cells presumed to be
glia in cerebral cortex of cat. J. Neurophysiol. 36, 879–892.
41. Janigro, D., Gasparini, S., D’Ambrosio, R., McKhann, G. M., and DiFrancesco, D. (1997)
Reduction of K+ uptake in glia prevents LTD maintenance and causes epileptiform activ-
ity. J. Neurosci. 17, 2813–2824.
42. Sypert, G. W. and Ward, A. A. (1971) Unidentified neuroglia potentials during propa-
gated seizures in neocortex. Exp. Neurol. 33, 239–255.
43. O’Connor, E. R., Sontheimer, H., Spencer, D. D., and de-Lanerolle, N. C. (1998) Astro-
cytes from human hippocampal epileptogenic foci exhibit action potential-like responses.
Epilepsia 39, 347–354.
44. Bordey, A., Sontheimer, H., O’Connor, E. R., Sontheimer, H., Spencer, D. D., and
de Lanerolle, N. C. (1998) Properties of human glial cells associated with epileptic sei-
zure foci Astrocytes from human hippocampal epileptogenic foci exhibit action poten-
tial-like responses. Epilepsy Res. 1–2, 286–303.
45. Lee, S. H., Magge, S., Spencer, D. D., Sontheimer, H., and Cornell-Bell, A. H. (1995)
Human epileptic astrocytes exhibit increased gap junction coupling. Glia 15, 195–202.
46. MacFarlane, S. N. and Sontheimer, H. (1997) Electrophysiological changes that accom-
pany reactive gliosis in vitro. J. Neurosci. 17, 7316–7329.
46a. Orkand, R. K. (1966) Effect of nerve impulses on the membrane potential of glial cells in
the central nervous system of amphybia. J. Neurophysiol. 29, 788–806.
47. Jan, L. Y. and Jan, Y. N. (1997) Voltage-gated and inwardly rectifying potassium chan-
nels. J. Physiol. (Lond.) 505, 267–282.
48. Wible, B. A., Taglialatela, M., Ficker, E., and Brown, A. M. (1994) Gating of inwardly
rectifying K channels localized to a single negatively charged residue. Nature 371, 246–249.
49. Robertson, B. (1997) The real life of voltage-gated K+ channels: more than model
behaviour. Trends Pharmacol. Sci. 18, 474–483.
50. Meir, A., Ginsburg, S., Butkevich, A., Kachalsky, S. G., Kaiserman, I., Ahdut, R.,
Demirgoren, S., and Rahamimoff, R. (1999) Ion channels in presynaptic nerve terminals
and control of transmitter release. Physiol Rev. 79, 1019–1088.
51. Levitan, I. B. (1999) Modulation of ion channels by protein phosphorylation. How the
brain works. Adv. Second Messenger Phosphoprotein Res. 33, 3–22.
52. Amzica, F. and Steriade, M. (2000) Neuronal and glial membrane potentials during sleep
and paroxysmal oscillations in the neocortex. J. Neurosci. 20, 6648–6665.
53. Wadman, W. J., Juta, A. J. A., Kamphuis, W., and Somjen, G. G. (1982) Current source
density of sustained potential shifts associated with electrographic seizures and with
spreading depression in rat hippocampus. Brain Res. 570, 85–91.
54. Somjen, G. G. (1995) Electrophysiology of mammalian glial cells in situ, in Neuro-
glia (Kettenmann, H. and Ransom, B. R., eds.), Oxford University Press, New York,
pp. 319–331.
55. Somjen, G. G. (1979) Extracellular potassium in the mammalian central nervous system.
Annu. Rev. Physiol. 41, 159–177.
56. Lux, H. D., Heinemann, U., and Dietzel, I. (1986) Ionic changes and alterations in the
size of extracellular space during epileptic activity, in Advances in Neurology (Delgado-
Escueta, A. V. and Ward, A. A., eds.), vol. 44, Raven, New York, pp. 619–639.
57. Largo, C., Cuevas, P., Somjen, G. G., Martin del Rio, R., and Herreras, O. (1996) The
effect of depressing glial function in rat brain in situ on ion homeostasis, synaptic trans-
mission, and neuron survival. J. Neurosci. 16, 1219–1229.
58. Lux, H. D. and Neher, E. (1973) The equilibration time course of [K] in rat cortex.
Exp. Brain Res. 17, 190–205.
59. Blanco, R. E., Marrero, H., Orkand, P. M., and Orkand, R. K. (1993) Changes in ultra-
structure and voltage-dependent currents at the glia limitans of the frog optic nerve fol-
lowing retinal ablation. Glia 8, 97–105.
60. Kuffler, S. W., Nichols, J. G., and Orkand, R. K. (1966) Physiological properties of glial
cells in the central nervous system of amphibia. J. Neurophysiol. 29, 768–787.
61. Orkand, R. (1986) Glial-interstitial fluid exchange. Annu. NY Acad. Sci. 4, 269–272.
62. Orkand, R. K. (1966) Effect of nerve impulses on the membrane potential of glial cells in
the central nervous system of amphybia. J. Neurophysiol. 29, 788–806.
63. Ransom, B. R. and Orkand, R. K. (1996) Glial-neuronal interactions in non-synaptic areas
of the brain: studies in the optic nerve. Trends Neurosci. 19, 352–358.
64. Kuffler, S. W. (1967) Neuroglial cells: physiological properties and a potassium medi-
ated effect of neuronal activity on the glial membrane potential. Proc. R. Soc. Lond. B.
Biol. Sci. 168, 1–21.
65. McKhann, G. M., D’Ambrosio, R., and Janigro, D. (1997) Heterogeneity of astrocyte
resting membrane potentials revealed by whole cell and gramicidin-perforated patch
recordings from cultured neocortical and hippocampal slice astrocytes. J. Neurosci. 17,
6850–6863.
Neuronal Energy Requirements 25
2
Neuronal Energy Requirements
Avital Schurr
1. NEURONAL ENERGY DEMANDS, SUBSTRATES,

AND ENERGY GENERATION
Descriptions of cerebral energy requirements found in the literature may confuse
many readers. On one hand, Hawkins (1) states that, “Although nervous tissue does not
participate in processes that require large amounts of energy, such as mechanical work,
osmotic work, or extensive biosynthesis, it has almost as high a rate of oxidative
metabolism as some tissues that do.” On the other, Clarke and Sokoloff (2) assert that,
“Although it is sometimes stated that the brain is unique among tissues in its high
rate of oxidative metabolism, the overall cerebral metabolic rate for O2 (CMRO2) is of
the same order as the unstressed heart and renal cortex.” These two contrasting views
are not necessarily contradictory. Whether or not the brain has higher energy require-
ments than other tissues, the brain is unique, both in its energy-demanding functions
and the limitations on the types of fuels it uses and their routes of delivery. The above
statements are also indicative of the reason brain-energy metabolism has developed
into a separate specialty, in which the energy supply and demand of the brain are stud-
ied as the basis for many brain dysfunctions and disorders. The past 15 years witnessed
several discoveries and new developments in the field of cerebral energy metabolism,
which could explain some of the brain’s unique energy requirements, and provide a
better understanding of various brain disorders.
1.1. Neuronal Energy Requirements, Energy-Demanding Functions,
and Energy Substrates
1.1.1. Neuronal Energy Requirements and Energy-Demanding Functions
The majority of the energy-demanding reactions in the brain belong to two catego-
ries: biosynthesis and transport. The biosynthesis of macromolecules, such as proteins,
polypeptides, and lipids, occurs mostly in cell bodies; that of smaller molecules, such
as neurotransmitters, occurs in nerve terminals. Of the multiple transport processes
that take place in the brain, ion transport is believed to demand the most energy (as
high as 50–60% of all brain-energy-consuming processes) (1). Of these, the mainte-
nance of sodium ions (Na+) and potassium ions (K+) gradients is the most demanding.
Unlike other tissues, the central nervous system (CNS) stores only minute amounts of
endogenous fuel. Brain tissue glucose levels at any given time are much lower than
From: The Neuronal Environment: Brain Homeostasis in Health and Disease
Edited by: W. Walz © Humana Press Inc., Totowa, NJ
25
26 Schurr
blood glucose levels (1–2 µmol/g brain wet wt, compared with 5–6 µmol/mL blood)
(1). Glycogen stores are not much higher than the glucose stores (2–3 µmol/g wet wt).
Cahill and Aoki (3) suggested that the required large ratio of water:glycogen (3–4 mL
water/1 g glycogen) could cause great fluctuations in volume, which are restricted
because of the rigidity of the cranium. Astrocytes are the main source of brain glyco-
gen, a fact that led many (1) to suggest that glycogen is not a readily available energy
source to neurons. As will be discussed later in this chapter, this view is now changing:
New data indicate that shuttle systems exist between astrocytes and neurons for differ-
ent metabolites. Estimates are that the total brain supplies of both glucose and glyco-
gen are sufficient for no more than 5 min of normal oxygen (O2) consumption, a period
that could get even shorter when excessive energy utilization and blood glucose sup-
plies cannot keep up with the demand. With no O2 reserves, the brain depends on the
blood and its flow, for all its O2 needs, extracting almost one-third of the total blood O2
under normal conditions. Consequently, blockade or reduction in blood flow would
diminish cerebral energy metabolism, because of O2 deprivation before any diminution
of glucose supply is apparent.
1.1.2. Energy Substrates
As mentioned, the bulk of the energy manufactured by the brain is devoted to
nerve excitation and conduction. These two functions are dependent on sustained mem-
brane potential, and, hence, most of the brain’s energy is consumed by ion transport.
Since the brain’s energy stores are limited, an unhindered flow of glucose and O2 is a
prerequisite for continuous, uninterrupted production of adenosine triphosphate (ATP).
This concept, i.e., that the normal substrates of cerebral energy metabolism are glucose
and O2 and the products are carbon dioxide (CO2) and water (2), has not changed in
decades, and generally is correct, although, as is explained below, it is an oversimpli-
fied one. Consequently, glucose utilization in the brain is regarded as obligatory (2).
Thus, the brain is considered to be different from other tissues, which are much more
flexible in their ability to utilize alternative fuels to glucose. This conclusion is based
on measurements of positive arteriovenous differences only, for glucose and O2, and
consistent negative values only, for CO2. Normally, neither positive nor negative arte-
riovenous differences can be demonstrated for lactate or pyruvate. Although the lack of
positive differences indicates that the brain does not utilize bloodborne lactate or pyru-
vate as aerobic energy substrates, the lack of negative differences for at least one of
these two products, even during a moderate O2 shortage, is intriguing, and could bear
potentially important implications.
Table 1 encapsulates the stoichiometric relationship between glucose utilization and
O2 consumption. The values in Table 1 are calculated medians of measurements
reported in the literature, and glucose equivalent of O2 consumption is the theoretical
one (6 mol O2/mol glucose) (2).
The normal conscious human brain consumes 156 µmol O2/100 g tissue/min. A simi-
lar CO2 production yields a respiratory quotient of 1.0. As indicated in Table 1, 156 µmol
of O2 (or CO2) are equivalent to 26 µmol glucose (based on a ratio of 6 µmol O2 con-
sumed for 1 µmol glucose utilized). Not withstanding, the measured rate of glucose
utilization is 31 µmol/100 g tissue/min, a surplus of 5 µmol glucose, which brings
down the O2:glucose ratio from the theoretical 6.0, to 5.5. The discrepancy between the
Table 1
Stoichiometric Relationship Between Glucose Utilization
and O2 Consumption in Normal Young Adult Mana
Rate
Function (µmol/100 g brain tissue/min)
Glucose utilization 31
O2 consumption 156
CO2 production 156
Glucose equivalent of O2 consumption 26
(6 mol O2/mol glucose for complete oxidation)
aAdapted from ref. 2.
calculated and the measured O2:glucose has remained unexplained, although it has
been suggested that the extra, nonoxidized glucose is converted to lactate, pyruvate,
and other intermediates of carbohydrate metabolism (2). Moreover, it has been postu-
lated that these intermediates are released from the brain into the blood in such minute
amounts that they are not detectable as a significant arteriovenous difference (2).
There are two “facts” supporting the claim that glucose is the only energy substrate
that the normal brain utilizes. The first is a respiratory quotient of 1.0 (6 mol O2 con-
sumed and 6 mol CO2 formed, a quotient that requires a stoichiometric consumption of
6 mol O2 for every mol glucose utilized, and thus a ratio of O2/glucose of 6.0). The
second is the inability to detect a positive arteriovenous difference for any other poten-
tial energy substrate.
Clarke and Sokoloff (7) warn their readers about the discrepancies between in vivo
and in vitro results concerning brain tissue, and the great hazard of extrapolating from
in vitro data to conclusions about in vivo metabolic function. In vitro systems bypass
functions, such as blood flow, but the uniqueness of the brain in vivo stems from the
blood–brain barrier (BBB). The assumption that BBB-devoid cerebral tissue, as with
in vitro systems, behaves differently from the same tissue in vivo has triggered great
skepticism toward many in vitro findings, especially among investigators who use only
in vivo systems. Do in vitro systems deserve such skepticism? Are warnings about
their pitfalls warranted? The answer to both questions should be affirmative, when
crushed tissue preparations, or mitochondrial, synaptosomal, or any other organelle-
enriched preparations are concerned. However, many in vitro preparations today main-
tain whole cells, partial or complete brain regions, and even a whole, perfused brain for
hours and days, intact and functional. These in vitro preparations deserve attention,
and should be given the chance to prove themselves before anyone blindly criticizes
data that have been originated by them. Therefore, this chapter describes data on energy
metabolism generated using in vivo systems, along with data produced by in vitro
preparations, such as cell cultures, excised CNS nuclei, and brain slices.
If one is to adhere to the premise that the brain is restricted in its choice of energy
substrates, because of the BBB, one need measure only glucose and O2 consumption
and CO2 production to calculate the brain’s energy needs. In vivo studies, at least until
recently, did just that: measuring what went into the “box” and what came out of the
box. Although, ironically, the intricate processes within the box, which are responsible
28 Schurr
for the consumption of glucose and O2, and the production of CO2, were elucidated
using in vitro systems, one could ignore them entirely when measurement of energy
metabolism in vivo is concerned. It is only in the last 15 yr that in vivo measurements,
both in humans and animals, have strongly suggested that brain energy metabolism is
not simply C6H12O6 + 6O2 = 6CO2 + 6H2O. As the methods of measuring brain func-
tion improve, insights are gained that provide a more complex and elaborate picture.
Recent studies indicate that, under conditions of cerebral stimulation, intracerebral
lactate increases to significantly higher levels than those under resting conditions (4–9).
These results confirm what was suspected for many years, i.e., that phasic changes in
neural activity are supported by glycolysis (10). As early as 1937 (11,12), it was noted
that local tissue O2 levels increase, rather than decrease, during spontaneous focal sei-
zures in human cerebral cortex. Rapid eye movement sleep caused large increases in
blood flow (13) and glucose utilization (14), but a decrease in O2 extraction (15). Fig-
ure 1 shows the cerebral metabolic rate (CMR) data in humans (5) under resting condi-
tions and upon stimulation. In whole brain under resting conditions, CMRO2 and
CMRglucose values were 1.50 and 0.37 µmol/min/100 g, respectively: a molar ratio of
4.1:1. In the visual cortex, under resting conditions, CMRO2 was 1.71 µmol/min/100 g
and CMRglucose was 0.42 µmol/min/100 g, or, again, a molar ratio of 4.1:1. Upon visual
stimulation the CMRglucose value rose a mean of 0.21 µmol/min/100 g (51%), and
CMRO2 value increased by a mean of only 0.08 µmol/min/100 g (5%), to produce a
molar ratio, for the increases, of only 0.4:1. These results indicate that the brain, under
working (stimulated) conditions, is capable of producing large amounts of lactate (via
pyruvate), up to 250% of control. This accumulated lactate remains in the brain, and
could later be used aerobically for energy metabolism under resting conditions. Other
recent studies show significant increases in lactate levels in human visual cortex (7,8)
and in rat hippocampus and striatum, on physiological stimulation (9).
Thus, although the impermeability of the BBB to lactate is irrelevant, since the bulk
of brain lactate is produced in the brain itself, the claim that the BBB is impermeable to
lactate is inaccurate, at best. Lactate entry to the brain via the arterial blood is consid-
ered to be negligible, but Rowe et al. (16) showed that, immediately after a carbo-
hydrate-rich meal, the higher-than-average lactate blood levels diminished on passing
the brain. A relatively high brain uptake index value for lactate has been reported when
a low lactate concentration (0.011 mM) was injected into the carotid artery of adult rats
(17–19). If the normal plasma level of lactate is 1.0 mM (20), one could expect brain
uptake index for lactate to be even higher. Several studies clearly demonstrate the abil-
ity of lactate to quickly permeate the adult BBB (18,21–24) via a stereospecific trans-
porter (18,22). A recent study used [3-13C]lactate to demonstrate that the average uptake
of lactate during the first 5 min after its injection (iv) to mice was almost 7× higher
than the previously calculated Vmax for uptake of lactate across the BBB (25a).
Since normal lactate concentration in cerebrospinal fluid exceeds (1.6–2.0 mM) the
plasma lactate level (1.0 mM) (20), and the CMRO2:CMRglucose under resting condi-
tions is higher (4.1) than that during cerebral stimulation (2.8), it is obvious that the
normal brain produces large amounts of lactate. Moreover, CMRO2:CMRglucose of 4.1
(5) is not the expected ratio of 6.0, or even 5.0. CMRO2:CMRglucose values of 5.0 or 4.0
indicate that 17 or 33%, respectively, of the glucose are consumed via nonoxidative
metabolism and converted to lactate, and that, under cerebral stimulation, when these
Fig. 1. The ratio of human cerebral metabolic values of oxygen (CMRO2) and glucose
(CMRglucose) in whole brain and in visual cortex, under resting conditions and during stimula-
tion with a reversing checkerboard stimulus. Under resting conditions, the CMRO2:CMRglucose
for the whole brain and the visual cortex were identical (4.1.). However, during stimulation, a
significant decrease in this ratio (to 2.8) was observed; the CMRglucose rose by a mean of 0.21
µmol/min/100 g (51%); the CMRO2 rose by a mean of only 0.08 µmol/mi/100 g (5%). This is
a molar ratio for the increase in metabolic rate of only 0.4:1. (Modified with permission from
ref. 5.)
values are falling to approx 0.4 (5), 93% of the metabolized glucose is being converted
to lactate. Such high production of lactate by the normal brain would explain the higher
concentration of lactate in CSF than in plasma (20). Hence, the normal brain continu-
ously produces large amounts of lactate.
If lactate is being produced in the brain regularly as an end product, it should either
accumulate there or appear in the venous blood that exits the brain. But in fact neither
occurs. A simple explanation for this would be an immediate aerobic cerebral utiliza-
tion of lactate under resting conditions. Alternatively, lactate could be converted to
glycogen, either via gluconeogenesis (25) or by direct conversion (25,26). Pyruvate,
the precursor of lactate, is as efficient an energy substrate as lactate, it is transported
via the same stereospecific transporters that transport lactate, and it is the product that
lactate has to be converted to before it can be utilized aerobically. Nevertheless, pyruvate
does not accumulate in the brain, and thus the pyruvate:lactate ratio is usually very small.
Before examining in vitro data on lactate as a cerebral energy substrate, two argu-
ments should be reconsidered, that blunt somewhat the warning by Clarke and Sokoloff
(2) on the limited usefulness of information extracted from in vitro systems resulting
from their lack of an intact BBB. First, as has already been pointed out, most, if not all,
of the cerebral lactate is produced by the brain itself, and thus the presence or absence
of the BBB is irrelevant. Second, as has been shown by the studies mentioned above
30 Schurr
(16,18,21–24), the BBB is permeable to lactate, although not to the same degree as
glucose. Hence, the relevance and the importance of the in vitro findings described
below should not be overlooked.
As early as 1953, McIlwain (27,28) was able to demonstrate the ability of guinea pig
cortical slices to respire when lactate was the substrate. When such slices, prepared
either from guinea pig or rabbit brain, were respiring in glucose-containing media,
lactate accumulated in the media (29). This lactate accumulation was initially rapid
(50 µmol/g/h), and fell after some minutes, to about 25% of the initial rate of accumu-
lation. This decline results from lactate being served as an oxidizable substrate, when
its levels are greater than 3 mM (30). Other in vitro results show 2 mM to be the mini-
mal lactate concentration that rat hippocampal slices can utilize for energy production
(31). The increase in brain lactate levels that accompanies increased cerebral activity,
both in humans (4,5) and animals (9), has been demonstrated in vitro as a 2–10-fold
increase in glycolysis induced by electrical stimulation or incubation with high potas-
sium (30). Thus, rates of lactate formation in vitro, of 100 µmol/g/h during electrical
stimulation, are typical, and can be sustained for hours. When the tissue was superfused
(3.5 mL/min), lactate formation values rose to 300 µmol/g/h (30). The normal rate of
lactate formation by human cerebral tissue in vitro is about 15–20% of the consumed
glucose (30).
Evidence published in 1988 (31) supports the idea that adult brain tissue is capable
of substituting lactate for glucose to fuel its normal function. Later studies (32–34)
reproduced that finding, demonstrating the ability of adult rat hippocampal slices to
utilize lactate (and pyruvate) as the sole energy substrate, upon complete depletion of
glucose from the incubation medium. Moreover, in those studies, the inhibition of
glycolysis with iodoacetate was ineffective in abolishing synaptic function in lactate-
supplemented slices, and completely diminishing such function in glucose-supple-
mented slices (31).
Cerebellar slices from adult rats exhibited an increase of approx 220% in their
ability to oxidize lactate to CO2, compared to cerebellar slices prepared from early
neonates (34). Moreover, at any age, the rate of CO2 production from lactate is over
300% higher (when slices were supplemented with 10 mM lactate) than the rate mea-
sured from glucose (when slices were supplemented with 5 mM glucose) (Fig. 2). These
findings are in agreement with the proposal that, thermodynamically, lactate is a pre-
ferred aerobic energy fuel, compared to glucose, since lactate conversion to pyruvate
requires no ATP investment; 2 mol ATP are consumed in the conversion of a mole of
glucose to pyruvate (31,35). Two recent studies (25,26) offer evidence that cultured
neonatal mouse astroglial cells are capable of using lactate for gluconeogenesis, and
that astroglia-rich primary cultures from neonatal rats are capable of supplying glyco-
gen-derived lactate to neighboring cells.
These in vitro studies strongly suggest a major role for lactate (and pyruvate) as a
substrate for cerebral energy metabolism. Based on studies with astrocytic and neu-
ronal cultures, Magistretti et al. (36–39) hypothesized that, when the presynaptically
released excitatory neurotransmitter, glutamate (Glu) is taken up by astrocytes, it stimu-
lates the production of glycolytic lactate and, consequently, the aerobic utilization of
lactate by neurons. The importance of lactate as an aerobic cerebral energy substrate
could become even greater under certain conditions, such as hypoxia/ischemia (see Sub-
Fig. 2. Conversion of glucose (5 mM) or lactate (10 mM) to CO2 by cerebellar slices pre-
pared from rats of different ages. (Modified with permission from ref. 34.)
heading 4.), as mentioned earlier. Although pyruvate is as useful as lactate for the
oxidative production of ATP, it does not accumulate in large quantities, as lactate does.
Thus, although pyruvate can support neuronal function in vitro, as a sole energy sub-
strate (32), its levels are too low to account for such support in vivo. Larrabee has
shown, using excised chick ganglia, that lactate metabolism competes with glucose
metabolism, and vice versa (40–42).
Other substances, such as the ketones, β-hydroxybutyrate and acetoacetate, could,
under certain circumstances, serve as energy substrates. Neonates have a great ability
to utilize these alternative substrates (2,43). In cases of diabetes or starvation, in which
blood levels of ketones are elevated, because of an increase in lipid catabolism, brain
tissue shows an adaptive ability to metabolize ketones as energy substrates, using
the same monocarboxylate transporters that transport lactate and pyruvate. Ketones
are usually converted to acetyl CoA, which directly enters the tricarboxylic acid
cycle (TAC).
Although glycogen stores in the brain are low, this polycarbohydrate is the main
energy reserve of the brain, and may be utilized during periods of high glucose
demands, when glucose supplies cannot keep up with the glycolytic flux. Such high
demands, as indicated in the previous subheading, occur regularly, upon increased neu-
ronal activity. It is a long-held dogma that the BBB limits the entry of glucose into
astrocytes and neurons during periods of high demands. We have shown, however,
using brain slices, in which the BBB is absent, that the rate of neuronal glucose entry is
too slow to keep up with its glycolytic consumption (44). If that is true, the role of
glycogen, found mainly in astrocytes in the adult brain, could be even more important,
especially if some or all of it is converted first to lactate (26) before being transported
32 Schurr
into neurons as an aerobic energy substrate (40–42). Calculations indicate that the gly-
cogen stored in brain tissue (3.3 µmol/g rat brain) could last for less than 5 min as the
sole energy source (2). However, in vitro results indicate that astrocytes are capable of
synthesizing glycogen from lactate (25), implying that the breakdown and synthesis of
glycogen could take place concomitantly.
As the rate of brain glycolysis increases, the level of glycogen’s first precursor,
glucose-6-phosphate (glucose-6-P) decreases, as the result of an enhancement in the
rate of fructose-6-P phosphorylation to fructose-1,6-diP, by the enzyme, phosphofruc-
tokinase. This enzyme is the main site of glycolytic regulation. Hence, with the reduc-
tion in glucose-6-P levels during periods of energy demands, glycogen synthesis also
declines. The uridine diphosphoglucose, formed from glucose-1-P, is the unit trans-
ferred and linked, via a α-1,4-glycosidic bond, to the terminal glucose on a nonreducing
side of an amylose chain. This reaction, catalyzed by glycogen synthetase, is the rate
limiting reaction of glycogen synthesis (2). On the degradation side of glycogen, most
of the phosphorylase is in its phosphorylated form, “a,” the active form of the enzyme.
Nevertheless, it is still unknown if and how glycogenolysis in the brain is regulated.
The hydrolysis of glycogen at the α-1,4-glycoside bond leaves a chain of α-1,6-glyco-
side linkages, upon which glycogen can be resynthesized. The hydrolysis of the α-1,6-
glycosidic chain by the debranching enzyme is slower than the hydrolysis of
α-1,4-glycosidic bonds, and its product is glucose. This reaction may be the rate-limit-
ing step in glycogenolysis. Approximately 1 mol free glucose is formed for each 11 mol
glucose-6-P released, when 1 mol glycogen is completely hydrolyzed. As is discussed
in Subheading 2., glycogen metabolism is tightly coupled to neuronal activity. It is
rapidly hydrolyzed during shortage in energy supply, and synthesized during adequate
supplies of glucose and O2.
2. COUPLING OF FUNCTION
AND ENERGY METABOLISM IN THE BRAIN
The assumption that activation of brain tissue is dependent on energy supplied by
oxidative metabolism of glucose was challenged over a decade ago (4,5). As has been
seen from the first subheading, magnetic resonance imaging measurements of glucose
consumption and concomitant calculations of O2 consumption from blood flow mea-
surements indicated a possible mismatch between the two, upon activation of the brain.
More recent studies (45,46) claim that no such mismatch exists, and that the initial
increase in glucose consumption, measured upon brain activation, is accompanied by a
similar increase in O2 uptake.
For years, elevated lactate levels have been considered to signal the existence of
hypoxia and anaerobic energy metabolism in tissues (47,48). Substantial evidence has
been accumulated (48,49) to indicate that large amounts of lactate can be produced in
many tissues under fully aerobic conditions, but brain tissue has been presumed to be
an exception. Lactate production has been promoted as an exclusively anaerobic pro-
cess, and its accumulation was thought to be a major detrimental factor in ischemic
brain damage (50).
Now, however, many studies (4–9,51) suggest that the brain is not necessarily dif-
ferent from other tissues, in that it does produce lactate under aerobic conditions. Upon
cerebral stimulation, intracerebral lactate increases to significantly higher levels than
those under resting conditions, both in humans (4,5,7,8,37,38) and rats (9). These
results confirmed what had been suspected for some time: Phasic changes in neural
activity are supported by glycolysis, a much less efficient ATP biosynthetic pathway
than the TCA and oxidative phosphorylation. Moreover, a recent study (52) has sug-
gested that, upon activation, a significant pool of lactate is available to the brain as a
source of energy. Nevertheless, as has been already mentioned, other studies demon-
strate a concomitant increase in O2 consumption upon activation, to match the increase
in glucose utilization. These studies disagree with the idea that increase in energy
demands by activated brain is met by glycolysis alone (45,46).
2.1. Glutamate, Neuro–Glial Interaction,
and Coupling of Function and Energy Production
Magistretti et al. (39), using primary cultures of mouse cerebral cortical astrocytes,
demonstrated the ability of Glu, the main excitatory neurotransmitter in the brain, to
stimulate glycolysis, i.e., glucose consumption and lactate production. They hypoth-
esized that Glu, released from active presynaptic neurons and taken up by astrocytes, is
the signal that couples neuronal activity to glucose utilization. According to this
hypothesis, astrocytic Glu uptake, via Na+ co-transport, activates the Na+/K+-ATPase
pump. Glu uptake from the synaptic cleft occurs through specific astroglial Glu trans-
porters, namely, Glu transporter 1 and astrocyte-specific Glu transporter (52). These
transporters show a stoichiometry of 3Na+ contransported with each Glu molecule.
The Na+-pumping activity, fueled with ATP formed by membrane-bound glycolytic
enzymes, increases glycolytic flux and, thus, glucose consumption and lactate produc-
tion. An additional ATP-requiring reaction takes place, upon Glu entry into astroglia,
i.e., Glu conversion to glutamine (GluNH2) by the astroglial enzyme, glutamine syn-
thase (52). Lactate, once released from astrocytes, is taken up by neurons to be utilized
aerobically as an energy substrate. Such a mechanism could explain the observed
increases in glucose utilization and lactate production, without a concomitant increase
in O2 consumption upon brain stimulation (4–7,48,49). Since neurons consume lactate
aerobically (31–34,53), any elevation in its levels should be short-lived.
The coupling of neuronal activity and energy metabolism has also been studied in
rat hippocampal slices (53). Although activation of these slices with Glu could result in
a significant elevation in the production of lactate, no such increase was detected. Does
this lack of increase in lactate tissue level indicate lack of lactate production, or that
lactate is consumed as quickly as it is produced? To test whether or not such elevation
occurs, lactate utilization must be prevented, or at least slowed down. One way to
block lactate use is to inhibit its transport from its site of production to its site of utili-
zation, i.e., from astroglia to neurons. As has been mentioned in Subheading 1., lactate
transport occurs via a specific MCT, located in the membrane of both astroglia and
neurons (54,55). The use of a specific inhibitor of this transporter, α-cyano-4-
hydroxycinnamate (4-CIN), has proved to be an efficient way to block lactate transport
into neurons (53,56). Upon activation of neurons with Glu in the presence of 4-CIN,
tissue lactate accumulation could be observed (Fig. 3). 4-CIN induced lactate accumu-
lation in brain slices, but it also prevented the recovery of normal neuronal function
after the removal of Glu (Fig. 3).
These results lead one to conclude that, under control conditions, any glycolytic
lactate formed during exposure to Glu is immediately consumed by neurons as an aero-
34 Schurr
Fig. 3. The content of glucose (bottom panel) and lactate (top panel), before (baseline) and
during exposure to Glu and during Glu washout, in control (open symbols) and 4-CIN-treated
(filled symbols) rat hippocampal tissue slices. Slices were supplied with artificial cerebrospinal
fluid containing 10 mM glucose. The recovery rates of neuronal function at the end of 30 min
washout in control (open bar) and 4-CIN-treated slices (filled bar) are shown at the right
of the bottom panel. Values are means ± SD. Significantly different from control (*p < 0.03;
**p < 0.0001).
bic energy substrate, and that lactate formation takes place mostly in astroglia. More-
over, lactate appears to be an energy substrate of utmost importance for neuronal re-
covery after activation. These conclusions are based on three facts: First, in the absence
of 4-CIN, no lactate accumulation was observed; second, when 4-CIN was present,
inhibition of lactate transport into neurons prevented its utilization, indicating that lac-
tate is produced outside the neuronal compartment; third, 4-CIN prevented the recov-
ery of neuronal function after activation, indicating that lactate could be an obligatory
energy substrate during neuronal activation. The blockade by 4-CIN of the neuronal re-
covery after exposure to Glu ensued, despite the ample supply of glucose (4–10 mM)
that was present throughout the experimental period.
The importance of glycolysis’s role, in the mechanism that couples brain activity
with energy metabolism, could be tested by glycolytic inhibition. Such inhibition
should weaken the ability of hippocampal slices to maintain neuronal function during
exposure to Glu, since glucose utilization would be blocked and lactate would not be
Fig. 4. A schematic diagram of the two main pathways of energy metabolism (glycolysis
and oxidative phosphorylation), in neuronal and astroglial compartments, during rest (left) and
during activation (right). For more details, see text.
produced. When 2-deoxy-D-glucose (2DG), a nonmetabolizable analog of glucose, was

supplied to slices, instead of glucose during exposure to Glu, neuronal function did not
recover upon Glu washout. However, when lactate was supplemented along with 2DG,
more than 50% of the slices showed neuronal function after Glu washout. This out-
come indicates that lactate plays a crucial role in assuring the preservation of neuronal
viability during periods of brain tissue activation and/or overactivation. Notwithstand-
ing, a recent study (57) claims that lactate is capable of inhibiting glial oxidative glu-
cose metabolism, and consequently O2 consumption, by up to 40%.
The following scenario (Fig. 4) can be drawn for brain energy metabolism during
resting state and during activation (exposure to Glu). During the brain’s resting state,
most of the glucose taken up from blood supply is metabolized aerobically, both in the
astroglial and the neuronal compartments. Under resting conditions, the astroglial pro-
duction of lactate usually exceeds that of neurons, mostly because of the higher activity
of ion pumping via the Na+,K+-ATPase pump (36–39,43,52). The majority of this lac-
tate is being transported into neurons, and directly enters the neuronal TCA. Upon
activation (with Glu), astroglial Glu uptake immediately ensues, accompanied by Na+
transport (36–39,43,52). The need to pump out the extra Na+ brings about a dramatic
increase in glial Na+, K+-ATPase activity, and thus an equally dramatic increase in
glucose consumption, most of which is glycolytic. This increased glycolytic activity is
not accompanied by an increase in O2 consumption, since lactate is its main product.
36 Schurr
The large amount of astroglial lactate produced under conditions of activation is

handled by two MCT systems. First, lactate is released from glia via the glial MCT
system. Second, it is transported into neurons via the neuronal MCT system, where it
becomes the main aerobic energy substrate. Thus, the increase in lactate utilization
causes a decrease in neuronal glucose utilization (40–42). This scenario could explain
the observation made by many investigators, that the stimulation of brain tissue
increases glucose uptake and consumption, without a concomitant increase in O2
consumption.
Are neurons intrinsically programmed to utilize lactate during activation, or is it
simply the result of inadequate supply of glucose? To answer this important question,
one has to estimate the relative contribution of neurons to the total glucose consump-
tion of the brain. To determine this contribution, the basal (resting) and activation-
driven glucose consumption of both neurons and astroglia should be calculated, and
the ratio between these two populations of cells in the brain region of study must be
taken into account.
Studies (58–60) have shown that neurons occupy no more than 50% of the volume
of cerebral cortex. In most brain regions, astrocytes outnumber neurons 10:1 (52,59).
Taking into account that basal astrocytic glucose consumption is over 3× higher than
that of neurons (61), and that, during activation, this consumption increases signifi-
cantly (37,52), a picture emerges in which neuronal contribution to glucose consump-
tion during activation appears to be minor, if not negligible. Moreover, because of the
ratio of astrocytes to neurons (10:1) and the fact that, upon activation, most of the
consumed glucose is by astrocytic glycolysis, neurons appear to have no choice but to
use lactate as their oxidative energy substrate during activation: This is the only one
available to them. The following equations attempt to demonstrate this point.
Astrocytic Energy Substrate Consumption and Metabolite Production
glucose + 5O2 ——> 5CO2 + 5H2O + 0.33 lactate + 32ATP (Basal)
glucose ——> 2 lactate + 2ATP (Activation)

—————————————————————————————————
2 glucose + 5O2 ——> 5CO2 + 5H2O + 2.33 lactate + 34ATP (Basal + activation)
Neuronal Energy Substrate Consumption and Metabolite Production
glucose + 6O2 ——> 6CO2 + 6H2O + 38ATP (Basal)
2 lactate + 6O2 ——> 6CO2 + 6H2O + 34ATP (Activation)

These equations are based on several postulates. First, that CMRglucose:CMRO2 is
not the theoretical 6, but the practical 5, meaning that, under resting (basal) conditions,
astrocytes use approx 17% of their glucose to support the Na+,K+-ATPase pumping
activity, through glycolysis, while converting it to lactate. During activation, most if
not all of the consumed extra glucose, here assumed to be equal to its basal level, is
converted to lactate. Neurons, in contrast, may be capable of a CMRglucose:CMRO2
of 6, whether they utilize glucose or its astrocytic product, lactate, for oxidative
energy metabolism. If one relies on Begnami’s (59) estimate of astrocyte:neuron

ratio (10:1), the sum of CMRglucose and CMRO2 for the two cellular compartments
during activation is:
10 Astrocytes × (2 glucose + 5O2 ——> 5CO2 + 5H2O + 2.33 lactate + 34ATP)
1 Neuron × (2 lactate + 6O2 ——> 6CO2 + 6H2O + 34ATP)

————————————————————————————————
20 glucose + 56O2 ——> 56CO2 + 56H2O + 21.30 lactate + 374ATP)
The CMRO2:CMRglucose for the above sum is 2.8, the very value found by Fox et al.
(5) with activated human visual cortex. It is evident from these equations that 10 astro-
cytes produce enough lactate to provide for all the oxidative energy needs of one neu-
ron, with enough left over to create a pool of lactate (62).
Until an in vivo quantitative determination can be made of the contribution of each
of the two cellular compartments to the total glucose consumption, the question of
whether the main neuronal energy substrate is glucose or lactate will remain unan-
swered. Nevertheless, there is one additional point that must be considered here. With
all the lactate that astrocytes produce, does the relatively small number of neurons
account for the consumption of this lactate? Considering the above equations, it is clear
that neurons would consume only a fraction of the astrocytic lactate produced during
activation. However, since no change in the concentration of lactate can be detected in
the venous blood exiting the brain during activation (see also Subheading 3.), one must
assume that all the lactate produced in the brain is consumed by the brain. Hence, if not
the activated neurons, then other consumers, such as neurons of surrounding areas, and
even white matter and axons, could consume the rest of the lactate.
There is one additional observation that supports Magistretti’s hypothesis. Bittar et al.
(63) studied the distribution of lactate dehydrogenase (LDH) isozymes among neurons
(lactate consumers) and astrocytes (lactate producers). They used specific polyclonal
antibodies against LDH1, the isozyme found mostly in heart muscle, and LDH5, the
one found mainly in skeletal muscle. The antibody raised against LDH1, the isozyme
that converts lactate to pyruvate, stained human hippocampal and cortical neurons;
hippocampal and cortical astrocytes were immunoreactive with an antibody raised
against LDH5. Such selectivity in these two isozymes’ distribution indicates that
astrocytes in certain brain nuclei, such as the hippocampus and the cortex, contain
exclusively the LDH activity that converts pyruvate to lactate, and, as such, are prob-
ably very active glycolytically, producing large amounts of lactate. In contrast, the
neurons in these regions are enriched with LDH1, the isozyme that converts lactate
to pyruvate, typical of tissues that utilize lactate (and pyruvate) for manufacturing
energy via the TCA.
Although the greatest emphasis throughout this chapter has been on glucose and
lactate (and pyruvate) as the substrates of cerebral energy metabolism, both in rest and
during activation, one should not ignore the role played by glycogen. The turnover of
this polysaccharide in the brain is very rapid (43), and finely tuned to the energy needs
of the activated tissue (64,65). Astrocytic glycogen levels rapidly fall during brain
stimulation, but the opposite occurs when brain activity is depressed (43).
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Title: Social Civics
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CIVICS ***
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SOCIAL CIVICS
Books by William Bennett Munro

The Government of the United States
The Government of American Cities
The Government of European Cities
Principles and Methods of Municipal
Administration
JUSTICE
By Edward Simmons
This frontispiece is a reproduction of a famous mural
decoration in the New York Criminal Court House.
The background is the doorway of the criminal court
room. Justice stands before the entrance holding in
one hand the conventional scales as a token of
impartiality, and in the other hand a globe to symbolize
the world. Over her left shoulder is draped the national
flag. Condemnation and Acquittal are typified by the
two children, one of whom holds a sword, the other the
dove of peace.
It has been usual to prefigure the Goddess of Justice
with her eyes bandaged, in token of her immunity from
outside influence. Mr. Simmons, however, has here
portrayed Justice with her eyes uncovered, because
he believed that “Justice should have her eyes wide
open—particularly in New York City”.
The artist’s wife and two children were the models
for this painting.
JUSTICE. By Edward Simmons
Copyright by Edward Simmons. From a Copley

Print,
copyright by Curtis & Cameron, Boston.
Reproduced by permission.
SOCIAL CIVICS
BY
WILLIAM BENNETT MUNRO
PROFESSOR OF MUNICIPAL GOVERNMENT
IN HARVARD UNIVERSITY
AND
CHARLES EUGENE OZANNE

TEACHER OF CIVICS
IN THE CENTRAL HIGH SCHOOL, CLEVELAND, OHIO
NEW YORK
THE MACMILLAN COMPANY
1922
All rights reserved
PRINTED IN THE UNITED STATES OF AMERICA
Copyright, 1922
By THE MACMILLAN COMPANY
Set up and electrotyped. Published June, 1922

PREFACE
Many excellent textbooks are already available for the teaching of

civics. Why should another be added to the number? Wherein does
this book differ from the rest? What are its outstanding features?
The Plan. This book covers a wider range than most texts. It
includes not only a survey of governmental framework and functions,
but many topics which are ordinarily spoken of as questions in
economics, sociology, and international relations. The propriety of
including such topics scarcely requires a defensive argument
nowadays, for the old lines of demarcation in the social sciences are
rapidly breaking down. The problems of our complex modern
civilization pay no heed to technical boundaries. They are the joint
product of political, social, and economic forces. No one can get a
grasp of them if he lets his mind run on a single track. A well-
organized course in civics, or in the problems of democracy, should
acquaint the student with the great institutions, relations, and
principles which dominate the life of the community. To accomplish
this end it should carry him as far afield as need be.
The Method. Nevertheless, the main theme of this book is
American government. No matter what the topic under discussion,
the authors have tried to link it up with the drift and purposes of
governmental action and policy. This intimate and continuous
connection between public problems and public policy is the central
concept of the book; it is the thread which holds the various chapters
together. There are many winding roads in the broad domain of the
social sciences, but sooner or later they all lead through the realm of
government.
The authors have not tried to discuss every possible phase of their
subject. Questions of outstanding importance have been given the
right of way; minor matters have been relegated to the footnotes or
omitted altogether. Those who desire enlightenment upon the odds
and ends of government or economics can get it from an
encyclopedia. The primary aim has been to get the facts hitched up
to principles, and to set the principles in their right perspective. For
this reason considerable space has been given to problems which,
although international in their scope, are of profound importance to
the people of the United States.
The Arrangement. No two textbook writers seem able to agree as
to the proper order in which material should be arranged. But the
sequence of the chapters is not, after all, a matter of much
importance. No one feels under any obligation to finish the Book of
Deuteronomy before beginning to read the Acts of the Apostles. The
teacher who prefers to start with the civic activities rather than with
the organization of government should have no hesitation in doing
so. In this book, at any rate, each of the larger divisions of the
subject is treated independently, and does not depend upon the
others. Some schools devote a half year to civics, and a half year to
economics. Material adapted to such an arrangement can be
obtained by a slight transposition of the chapters.[1]
The Supplementary Material. More than a hundred pages are
devoted to lists of general references, group problems, short studies,
questions, and topics for debate. It is not anticipated, of course, that
any teacher can find time to use them all; but the endeavor has been
made to afford ample variety for selection. Among the general
references are included not only a few of the most authoritative and
most recent publications, but also some elementary books which can
ordinarily be found in the smaller school and public libraries. The
group problems are intended to be of special service to those
teachers who use the “project method” of instruction; but in any
event the practice of setting groups of pupils to work upon problems
of a comprehensive character is a good one for every teacher to
pursue at times. Some of these group problems are “projects” in the
strict sense of the term; others are merely research topics of an
elementary sort. Some involve field work; some do not. The
questions are not designed to be tests of memory, but to provide a
basis for socialized recitations, to provoke discussion, and to
encourage among the pupils the habit of forming their own opinions.
The numerous and varied topics for debate have been inserted with
the idea of lending encouragement to one of the most effective
methods of promoting interest in public problems.
The Point of View. In dealing with controverted questions, of which
there are a great many in the field of civics, the authors have tried to
hold the scales justly, and to give both sides a fair hearing. It may be
that they have not in all cases succeeded; if so, they can only plead
the unconscious partisanship to which all human flesh is heir. In any
event these chapters have been written with a sincere desire to
promote a more intelligent citizenship, with an abiding faith in the
merits of American government, and with the conviction that the
people of the United States will prove abundantly capable of solving
their manifold problems by the traditional process of reconciling
liberty with law.
The Illustrations. Apart from a number of diagrams, the illustrative
material has been drawn from the masterpieces of American mural
art. They symbolize what is best in our civilization; they may serve to
give pupils a passing acquaintance with a few creative works of
enduring value; and they have some artistic merit, which most
textbook illustrations have not. For the selection of these illustrations
and for the explanatory legends which accompany them, I am
indebted to my wife.
A Word of Acknowledgment. To Mr. Ozanne this book owes a
large part of whatever value it may possess. He has had a great deal
to do with the arrangement of materials and the methods of
presentation. Every page has had his repeated scrutiny. It is to me a
great pleasure to have had, in this work, the close co-operation of
one who possesses not only a mastery of the subject but a rare
proficiency in classroom methods.
WILLIAM BENNETT MUNRO.
Harvard University,
February 22, 1922.
CONTENTS
PAGE
Preface v
PART I
THE AMERICAN ENVIRONMENT
CHAPTER
I. Human Society 1
II. The People, Races, and Racial Problems of 19
the United States
III. Economic Factors and Organization 37
PART II
THE ORGANIZATION OF GOVERNMENT
THE FOUNDATIONS OF GOVERNMENT

IV. The Nature and Forms of Government 62
V. The Citizen: His Rights and Duties 78
VI. Popular Control of Government 94
THE ELECTORAL SYSTEM

VII. Suffrage and Elections 118
VIII. Party Organization and Practical Politics 145
LOCAL AND STATE GOVERNMENT

IX. Counties and Rural Communities 166
X. City Government 182
XI. Municipal Problems of Today 203
XII. State Government in Outline 226
NATIONAL GOVERNMENT
XIII. The National Constitution 246
XIV. Congress at Work 266
XV. The President and his Cabinet 286
XVI. The Courts and the Law 308
PART III
THE CIVIC ACTIVITIES
ECONOMIC
XVII. Natural Resources and Conservation 326
XVIII. The Agricultural Interests 339
XIX. The Encouragement and Regulation of 356
Commerce
XX. The Organization and Control of Industry 383
XXI. Labor and Labor Problems 400
XXII. Currency, Banking, and Credit 424
XXIII. Taxation and Public Finance 450
XXIV. Public Utilities and Public Ownership 474
SOCIAL
XXV. Education 492
XXVI. Public Health and Sanitation 514
XXVII. Poor-Relief, Correction, and Other 540
Welfare Problems
INTERNATIONAL
XXVIII. The National Defence 563
XXIX. Foreign Relations 587
XXX. The United States as a World Power 606
XXXI. The United States and the League of 625
Nations
XXXII. Political and Social Reconstruction 646
APPENDIX
The Constitution of the United States 665
INDEX
LIST OF ILLUSTRATIONS
Justice. By Edward Simmons Frontispiece

PAGE
The Family. By Charles Sprague Pearce Facing 12

The Melting Pot. By Vesper L. George ” 33
Thrift and Prosperity. By Frederick Dielman ” 50
Liberty, Fraternity, Equality. By Edward Simmons ” 78
Government. By Elihu Vedder ” 118
Good Administration. By Elihu Vedder ” 145
Washington at the Constitutional Convention. By ” 255
Violet Oakley
Science Revealing the Treasures of the Earth. By ” 329
Edwin A. Abbey
The Spirit of Vulcan. By Edwin A. Abbey ” 383
The Crowning of Labor. By John W. Alexander ” 400
The Evolution of the Book. By John W. Alexander ” 492
Justice and Mercy. By A. R. Willett ” 554
The Spirit of Light. By Edwin A. Abbey ” 606
The Graduate. By Edwin H. Blashfield ” 646
LIST OF MAPS, CHARTS, AND DIAGRAMS
PAGE
The Center of Population Facing 21

The Growth of American Cities ” 183
The City Manager Plan ” 197
Municipal Administrative Departments ” 205
Traffic Zones ” 210
Simplified State Administration ” 241
Land Regions of the United States ” 340
The Relation of Money and Prices ” 443
The National Debt, 1860-1920 ” 467
The Control of Education ” 500
The Rise of Prices in War Time ” 582
SOCIAL CIVICS
CHAPTER I
HUMAN SOCIETY
The purpose of this chapter is to explain why human beings have come
together into a society, to point out some of the chief influences which affect
their action in organized groups, and to show that government is the greatest
of the agencies through which human co-operative action is maintained today.
Man’s Place on the Earth.—The present The supremacy of
organization of society finds its explanation in man.
the nature of man. Man is by nature a social being; he possesses
intelligence and the capacity to organize. Among living creatures
man is by no means the first in physical power—he is neither so
strong as the lion nor so fleet as the reindeer. But he dominates the
earth because he more than makes up, by his mental and moral
superiority, for whatever may be lacking in physical prowess. We do
not know when mankind first began to assert its mastery over all
other forms of life on the earth, but it was a very long time ago.
Man’s superior intelligence gave him a start, and his capacity for
organization enabled him to clinch the victory. Today he is supreme
on land, at sea, and in the air.
The Principle of Development.—Human Evolution.
society did not come into existence all at once; it
has grown to its present form through the slow process of time.
Everywhere we see the principle of development at work—among
individuals and among institutions. Everything is still in a continual
process of change and this has unquestionably been the case for
many thousands of years. Or to put it in another way, new forms of
life and institutions are continually being evolved from older forms.
To understand this principle of continual Darwin and his
change and development it is necessary to know work.
something about the doctrine of evolution. This doctrine is commonly
associated with the name of Charles Darwin, for although many
others had hinted at the idea, he was the first to set it forth
accompanied by scientific evidence.[2] Darwin’s theory has been
much misunderstood; in the illiterate mind it is often summed up by
saying that “Man is descended from the monkey”. But Darwin did not
say anything of the kind, neither did he ever deny the existence of
God as the controlling factor in the life of the universe. Darwin’s
theory of evolution asserted that all forms of life now on earth have
sprung from a few simple, primitive types, and that human life is an
evolution from one of these earlier forms. Human institutions,
likewise, did not arise instantaneously but developed from simple
and primitive beginnings into their complex structure of today.
The evidence upon which the doctrine of Soundness of
evolution rests is too extensive and too technical Darwin’s theory.
to be even summarized here but it is regarded as trustworthy by
most scientists.[3] For fifty years it has been studied, discussed, and
tested by scholars with the result that educated men are now
disposed to accept the doctrine so far as its main principles are
concerned although they differ about various details.
It is astonishing how little we know, after all, about the beginnings
of things. We do not know when or how life began upon the earth.
We do not know the exact origin of man. But we do know that all
forms of life and institutions have grown; they were not created in the
shape we now have them. All the general laws of life which apply to
plants and animals apply also to man. Alike they are born, they are
nourished, they mature, and they produce descendants like
themselves.
The method of evolution, according to The principle of
Darwin’s theory is based upon the principle of “natural selection”
natural selection. It is a well-known law of nature and the struggle for
that “like begets like”, in other words that existence.
offspring resemble the parent-stock although there may be some
individual differences. If it were not so, a definite species would
never be perpetuated. All forms of life, moreover, reproduce
themselves more or less abundantly. It is said that the progeny of a
single starfish exceeds half a million per year. Even the elephants,
which are the slowest breeding of all animals, produce a sufficiently
numerous offspring to over-run the whole of Africa if every young
elephant grew to maturity.
But nowhere does the entire progeny of any organisms, whether
plants, animals, or human beings, survive to full growth. If every
acorn became an oak tree, there would in time be no room for
anything else on the surface of the earth. If every tadpole grew to be
a frog, there would be no room for anything else in the waters of the
earth. All life, however, is a struggle for existence, a relentless
competition for air, sunshine, moisture, and soil on the part of plants,
and for food and shelter on the part of animals. The further down we
go in the scale of life the more bitter this struggle for existence
becomes; small animals eat up the plants; large animals feed on the
smaller ones. Higher in the scale, the struggle is not so keen, and
among mankind it is the least strenuous of all.
In this struggle for existence, what plants and animals survive?
The answer is that those which are best fitted to their environment
continue to exist and to reproduce themselves, while those which are
more poorly adapted to their environment fall out of the race and
disappear. In other words natural selection or The survival of the
the survival of the fittest was thought by Darwin fittest.
to be the principle which determines the course of evolution. The
unfit perish and the fit survive, everything depending upon the
relative success of the organism in adapting itself to the conditions
under which it is endeavoring to live. The clumsy mastodon became
extinct; his bones are now relics in museums; but the horse, being
fleet of foot, managed to survive. The fit organisms,—plants or
animals or human beings,—have survived and have perpetuated the
species. They gave to their offspring the traits or qualities which
enabled themselves to survive. In that way each generation of
organisms became a little better fitted to its environment than the
generation which went before. This is a slow process for human
beings, of course, for it takes twenty years or more to produce a new
generation of men, whereas new generations of birds, reptiles, and
lower animals appear every few months. The principle of natural
selection, moreover, does not fully account for the form which
evolution has taken. Other factors have also been at work, but
scientists are not yet agreed as to their nature or importance.[4]
Now how does the human race figure in all Natural selection as
this? Mankind has also been at all times under applied to the
the necessity of adapting itself to its human race.
environment, and in the early stages of human history those who did
not successfully adapt themselves went to an early grave. During
century after century natural selection and the other factors
strengthened the race. As the race grew stronger in intelligence,
man undertook to subdue his environment rather than to be subdued
by it, and in considerable measure he succeeded. He discovered the
art of kindling a fire and made this element his servant in conquering
the cold. He domesticated wild animals, made them provide him with
milk and meat, and compelled them to carry his burdens. Step by
step he mastered the natural conditions which surrounded him. This
he did by his ability to work with his fellow-men. Through this power
of co-operation he created group organizations—society, the state,
and government.
The struggle for existence among men is not Today the strong
now, therefore, as it was in primitive days, a life- assist the weak.
and-death competition for food and shelter. Individuals have come to
recognize each other’s rights and to seek even their own advantage
by co-operation rather than by strife. The association of individuals in
the family and the community serves to preserve the weak whom a
keen struggle for existence would eliminate. Our whole system of
poor-relief, hospitals, and care for the defective is based upon the
idea of giving a fair chance to those who otherwise would be
crowded out of the struggle for existence altogether. The competition
today is not so much between individuals as among groups, small or
large, including competition between whole nations of men.
The Factors in Social Progress.—Two The relative
factors have greatly influenced the course of influence of
social evolution or social progress. These inheritance and
factors are inheritance and environment. By environment.
inheritance we mean the qualities, physical and mental, which each
generation inherits from the generation preceding. By environment
we mean the general surroundings, physical and social, in which the
people live. Mankind influences these surroundings to a
considerable extent and moulds them to his own needs, but in turn is
also influenced by them. Everything that is characteristic of man is
the result of these two forces, inheritance and environment. In some

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The neuronal environment: brain homeostasis in health and diease/edited by

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

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

LUIGI FRANCESCO AGNATI, Department of Human Physiology,

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

Stephen Dombrowski, Imad Najm, and Damir Janigro

Dombrowski, Najm, and Janigro

2. CELLULAR CORRELATES OF BRAIN HOMEOSTASIS

on atoms or small molecules flowing in aqueous solution. Separation of charges in an

sium and chloride homeostasis is likely to promote neuronal excitability by decreasing

these syncytia of neocortical astrocytes shared characteristics of both spatial buffering

4.3. Astrocytic Ion Currents and Potassium Homeostasis

been described in cultured astrocytes (74). A cardiac-type outward potassium current

Fig. 4. Neuronal stimulation induces abnormal accumulation of EC K+ and burst discharge

Fig. 5. Abnormal accumulation of EC potassium is caused by impaired glial homeostasis.

To summarize this brief synopsis on K+ buffering by glia: At least three independent

5. ION HOMEOSTASIS AND NEUROLOGICAL DISEASE

Fig. 6. (previous page) Immunocytochemical (ICC) localization of ERG channel protein in

1. NEURONAL ENERGY DEMANDS, SUBSTRATES,

produced. When 2-deoxy-D-glucose (2DG), a nonmetabolizable analog of glucose, was

The large amount of astroglial lactate produced under conditions of activation is

glucose + 5O2 ——> 5CO2 + 5H2O + 0.33 lactate + 32ATP (Basal)

glucose ——> 2 lactate + 2ATP (Activation)

Neuronal Energy Substrate Consumption and Metabolite Production

glucose + 6O2 ——> 6CO2 + 6H2O + 38ATP (Basal)

2 lactate + 6O2 ——> 6CO2 + 6H2O + 34ATP (Activation)

energy metabolism. If one relies on Begnami’s (59) estimate of astrocyte:neuron

1 Neuron × (2 lactate + 6O2 ——> 6CO2 + 6H2O + 34ATP)

Title: Social Civics

Author: William Bennett Munro

Release date: February 10, 2024 [eBook #72924]

Original publication: New York: The MacMillan Company, 1922

Credits: Charlene Taylor, KD Weeks,and the Online Distributed

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JUSTICE. By Edward Simmons

Copyright by Edward Simmons. From a Copley

CHARLES EUGENE OZANNE

Set up and electrotyped. Published June, 1922