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Glial Cells Under Physiologic and Pathologic Conditions
Pascal Kurosinski, Dipl Biol;
Jürgen Götz, PhD
Arch Neurol. 2002;59:1524-1528.
ABSTRACT
Glial cells have long been considered to play roles in the nervous system
that are unexciting compared with those of neurons. They provide neurons with
nutrients, guide migrating neurons and their precursors during development,
and dispose of the brain's "waste." Recent evidence, however, suggests that
glial cells play more sophisticated, neuronlike roles. They integrate neuronal
input, modulate synaptic activity, and process signals related to learning
and memory. These findings have significant implications for humans with neurodegenerative
diseases. In addition to activation on nervous system injury and during neuronal
degeneration, glial cells also degenerate in several neurodegenerative diseases.
Therefore, glial cell loss may contribute to the impairment of learning and
memory. Therapeutic approaches to combat human neurodegenerative diseases
thus need to restore the function of both neurons and glial cells.
INTRODUCTION
The importance of neurons for central nervous system (CNS) function
is unquestionable. To assess the potential role of glial cells, phylogeny
may provide a clue. In the nematode Caenorhabditis elegans, for example, a total of 302 neurons but only 56 glial and supporting
cells have been identified. As one rises through phylogeny, the ratio of glia
to neurons increases, and in humans, the brain contains the highest ratio
of glia to neurons (at least 10:1). Consequently, one is tempted to suggest
that glial cells play important roles in higher cognitive functions.
Glial and neuronal cells arise from progenitors that are initially multipotent
but gradually become restricted to the neuronal or glial lineage. Differentiation
occurs in a stereotyped sequence whereby neurons are generated first, followed
by glial cells, which differentiate after neurogenesis is largely completed.
Glial cells of the CNS can be divided into microglia and macroglia. Microglia
are macrophagelike cells that serve a phagocytic function. Macroglia are composed
of astrocytes and oligodendrocytes, which are the CNS equivalent of myelinating
Schwann cells that are found in the peripheral nervous system. In close association
with neurons, astrocytes enwrap synaptic terminals and make extensive contacts
with endothelial cells from the capillaries. Moreover, astrocytes are interconnected
with one another by gap junctions. In the dentate gyrus of the hippocampus,
they give rise to new neurons throughout life in many vertebrates, including
humans.1
Historically, glial cells were assigned several functions in supporting
neurons during development and throughout life. Glial control of the survival
of associated neurons is dependent on prior neuronal triggering of glial cell
fate commitment and trophic factor expression. In addition, glial cells control
the migration of neurons during development. Embryonic neurons are typically
born at some distance from their final sites in the mature nervous system.
The pathways taken by newborn neurons are specific and depend on cellular
contacts and diffusible guidance cues, most of which are provided by glial
cells and their precursors. Development and lamination of the mammalian neocortex
is controlled by a set of specialized neuroepithelial radial glial cells that
provide the migration scaffold used by roughly 90% of cortical neurons. Several
lines of evidence indicate that these radial glia are the precursors of astrocytes
in the mature brain. An analogous process occurs during the migration of newborn
neuronal granule cells in the cerebellum along Bergmann glial processes from
the internal granule cell layer of the developing postnatal cerebellum.
NEURONAL PROPERTIES OF GLIAL CELLS
Additional, more elaborate functions were recently assigned to glial
cells. In the mature nervous system, examination at the ultrastructural level
reveals a tripartite structure involving the astrocyte that can be intimately
associated with the synapse and that literally enwraps many presynaptic and
postsynaptic terminals2 (Figure 1). This close physical relationship probably provides an
opportunity for many functional interactions between astrocytes and neurons.
As an astrocyte can make contacts with a neuron and a capillary, it has the
potential to shuffle nutrients and metabolites between the blood supply and
the active neuron (Figure 1). Furthermore,
as a single astrocyte can make contacts with multiple neurons, these nonneuronal
cells are positioned to provide information transfer between neighboring neurons.
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Figure 1. Glial cells under physiologic
conditions in the adult brain. Astrocytes make contacts with neurons and capillaries
and shuffle nutrients between the blood supply and the active neuron. As a
single astrocyte can make contacts with multiple neurons, these nonneuronal
cells are positioned to transfer information between neighboring neurons.
Examination at the ultrastructural level (inset) reveals a tripartite structure
involving the astrocyte that can be intimately associated with the synapse
and enwraps many presynaptic and postsynaptic terminals. Astrocytes integrate
neurotransmitter inputs and release their own transmitters that act on neighboring
neurons. Astrocytes communicate with each other using gap junctions and neurotransmitter-mediated
signaling. Adapted in part from Haydon.3
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In the stratum radiatum hippocampi, for example, about 50% of the synapses
have astrocytic processes, and in 30% of the synapses, an astrocyte process
separates 2 neighboring synapses (Figure 1). In addition, astrocytes almost exclusively surround synapses
that have a high probability of neurotransmitter release.
Astrocytes express functional receptors for many different neurotransmitters.
Binding to these receptors leads to changes in intracellular calcium levels
and even to oscillations in internal calcium levels. Many of the initial studies
that demonstrate calcium excitability of astrocytes were performed in cell
culture, but studies using acutely isolated brain slices and later acutely
isolated hippocampi have supported the calcium excitability property of astrocytes.
As astrocytes possess a number of neurotransmitter receptors coupled to intracellular
calcium mobilization, neuronal activity may regulate astrocytic calcium levels.4 Indeed, several laboratories have demonstrated that
astrocytes and perisynaptic Schwann cells respond to synaptic activity through
the activation of glial receptors.3
In addition to integration of neurotransmitter input, astrocytes release
their own transmitters that act on neighboring neurons and modulate their
function, suggesting a bidirectional signaling pathway between astrocytes
and neurons (Figure 1). If glial
cells can release neurotransmitters in a regulated manner, this process must
be a fundamental component of their dialogue with neurons during synaptic
activity.
A compartmentalization reminiscent of that of neurons has been demonstrated
for the cerebellar Bergmann glia. These highly ramified glial cells consist
of hundreds of independent compartments, called microdomains, that are capable of autonomous interactions with the particular group
of synapses they enwrap. Stimulation of adjacent parallel fibers induces localized
elevations of intracellular calcium levels in the Bergmann glia.5
ROLE IN MEMORY AND LEARNING
What is the role of glial cells in memory and learning? Studies in brain
slices showed that activation of astrocytes increased miniature inhibitory
postsynaptic currents in hippocampal pyramidal neurons. Astrocytes may therefore
be necessary in the activity-dependent modulation of inhibitory synapses in
the hippocampus.6 A role of astrocytes in synaptic
function is also supported by results of studies in mice lacking the intermediate-filament
glial fibrillary acidic protein (GFAP), a protein found predominantly
in astrocytes of the CNS. Although astrocytes were present in the CNS of the
mutant mice, they contained a severely reduced number of intermediate filaments.
Since astrocytic processes contact synapses and may modulate synaptic function,
McCall et al7 examined whether the hippocampal
CA1 region of GFAP-deficient mice was altered in long-term potentiation (the
increase in synaptic potential after brief high-frequency trains of stimulation).
The mutant mice indeed displayed enhanced long-term potentiation compared
with control mice. Therefore, these mice demonstrate that a primary defect
in astrocytes influences neuronal physiology.7
In a related study8 using another GFAP-deficient
mouse strain, excitatory synaptic transmission from parallel or climbing fibers
to Purkinje cells was unaltered in the cerebellum, and these synapses displayed
normal short-term synaptic plasticity to paired stimuli. In contrast, long-term
depression at parallel-fiber Purkinje cell synapses was clearly deficient,
suggesting a role for astrocytes in induction and maintenance of long-term
depression in the cerebellum.8
GLIAL CELLS IN DISEASE
Results of a recent quantitative postmortem investigation of the cerebral
cortex have convincingly demonstrated cortical glial cell loss in patients
with major depression. Evidence is also mounting that glial cell loss may
be a feature of schizophrenia. In addition, glial cells are heavily affected
in diseases with cognitive dysfunction related to Alzheimer disease. Hallmark
lesions of Alzheimer disease are extracellular amyloid plaques and intracellular
neurofibrillary tangles that are composed of hyperphosphorylated, filamentous
microtubule-associated tau protein. In the absence of amyloid plaques, neurofibrillary
tangles are also abundant in additional neurodegenerative diseases, including
Pick disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic
grain disease, and frontotemporal dementia with parkinsonism linked to chromosome
17 (FTDP-17).9 In contrast to Alzheimer disease,
in which hyperphosphorylated tau protein forms filaments only in neurons,
numerous tau filament–containing glial cells are present in many of
these diseases that are collectively termed tauopathies. These disease entities, all of which were previously defined as neurodegenerative
diseases, are now better considered glianeuronal disorders10-11
(Figure 2B). A recent analysis of
2 patients with the disease-causing FTDP-17–linked tau mutation N279K
showed widespread neuronal and glial tau accumulation in the cortex, basal
ganglia, brainstem nuclei, and white matter. In the neocortex, tau-immunoreactive
glial cells outnumbered immunoreactive neurons.12
The glial abnormalities of corticobasal degeneration include astrocytic plaques
and numerous tau-immunoreactive inclusions in the white matter (Table 1).
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Figure 2. Glial cells under pathologic conditions
in the adult brain. A, Reactive astrocytosis as a vigorous response to diverse
neurological insults, including viral infections, acute, chronic, and traumatic
brain injuries, and neurodegenerative diseases such as Alzheimer disease (AD).
The key histopathological hallmarks of AD, tau-containing neurofibrillary
tangles and amyloid plaques, induce astrocytosis and the activation of microglia,
which subsequently release cytokines. B, In many tauopathies, tau aggregates
are numerous in neurons and glial cells. In some brain regions of affected
individuals, the glial abnormalities outnumber the neuronal abnormalities.
Functional impairment of glial cells as a consequence of the deposits is likely
to affect glia-glia and glia-neuron interactions. C, Glial abnormalities of
Alexander disease. Eosinophilic deposits of glial fibrillary acidic protein
(Rosenthal fibers) are the key pathological hallmark of Alexander disease.
Again, functional impairment as a consequence of the deposits is likely to
affect glia-mediated interactions.
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Glial Cells in Neurodegenerative Diseases*
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Although it is likely that the glial abnormalities affect neuronal degeneration,
it is at present unknown whether they are required for a progression of the
disease and its clinical features.10, 12
Aspects of the glial tau abnormalities have been reproduced in a mouse model
that expresses the FTDP-17–associated tau mutation G272V under control
of a prion protein promoter–driven transactivator system. Transgenic
tau expression in oligodendrocytes was much higher than that in neurons. Oligodendroglial
G272V tau formed filaments and was phosphorylated at the tau phosphoepitope
AT8 that is diagnostic for Alzheimer disease.13
In related transgenic models that express wild-type or FTDP-17–associated
mutant forms of tau in neurons, the tau abnormalities were restricted to neurons,
but microglial and astrocytic cells were activated. In some of these transgenic
mouse models, microglia with phagocytosed myelin debris and myelin ovoids
were present, indicating wallerian degeneration.11
Together, these animal models are useful to study the pathophysiology and
prevention of tau filament formation in neurons and glial cells.
The only known late-onset neurodegenerative disease in which glial cell
inclusions constitute the predominant lesion is multiple system atrophy. Clinically,
multiple system atrophy includes olivopontocerebellar atrophy, striatonigral
degeneration, and Shy-Drager syndrome. The cytoplasmic inclusions are strongly
immunoreactive for  -synuclein and are found mainly in the cytoplasm
and, to a lesser extent, in the nucleus of oligodendrocytes (Table 1). The formation of glial cytoplasmic inclusions might be
the primary lesion that will eventually impair nerve cell function. Nerve
cell loss and clinical symptoms of multiple system atrophy in the presence
of only cytoplasmic inclusions have been described.14
Physiologic expression of tau and -synuclein proteins occur predominantly
by neurons.
Associated with the accumulation of insoluble protein aggregates in
various disorders, but also with injury in the nervous system, is the morphologic
activation of astrocytes and microglial cells, a process called reactive gliosis
(Figure 2A). After injury, brain
macrophages proliferate and function in tissue repair, including removal of
dead tissue and debris through phagocytosis. In addition, cytokines produced
by reactive microglia initiate a cascade of cellular responses that greatly
influence astrocytes. During this process, GFAP is up-regulated in astrocytes.
In a variety of conditions, including injury and neurodegenerative diseases,
the GFAP content of astrocytes at the site of injury or activation increases
until the astrocyte cell body and its processes are completely filled. These
reactive astrocytes repair damaged brain tissue and function in the reestablishment
of the integrity of the microenvironment surrounding the lesion.
In addition to degeneration during disease and reaction to injury of
the nervous system, glial alterations are the primary cause of the neuropathological
changes in some cases. Alexander disease is a rare disorder of the CNS of
unknown etiology.15 Infants with Alexander
disease usually die within the first decade of life; patients with juvenile
or adult forms typically experience ataxia, bulbar signs, spasticity, and
a more slowly progressive course (Table
1). The pathological hallmark of all forms of Alexander disease
is the presence of Rosenthal fibers, ie, cytoplasmic inclusions in astrocytes
that contain GFAP in association with small heat shock proteins (Figure 2C). Overexpression of human GFAP
in astrocytes of transgenic mice is fatal and accompanied by the presence
of inclusion bodies indistinguishable from human Rosenthal fibers. These results
suggest that a primary alteration in the GFAP may be responsible for Alexander
disease. Indeed, results of sequence analysis of DNA samples from patients
representing different phenotypes of Alexander disease showed that most cases
are associated with nonconservative mutations in the coding region of the
GFAP. Alexander disease therefore represents the first example of a primary
genetic disorder of astrocytes.15
TRANSPLANTATION APPROACHES TO TREAT HUMAN DISEASES
A common neuropathological feature of neurodegenerative diseases is
neuronal cell loss. In addition to pharmacological treatments, cellular grafting
approaches are currently undergoing evaluation for their therapeutic potential.
These approaches should appreciate the substantial cell loss in the glial
compartment in many of these diseases, but also that the cells that are routinely
used in grafting protocols have the potential to differentiate into neurons
and gliallike cells. Cell replacement therapies are currently used to treat
Huntington disease or Parkinson disease.16-17
For the latter, clinical trials have been initiated already by transplanting
human fetal brain tissue to substitute for the loss of dopaminergic neurons.
However, several aborted fetuses are required for the therapy in a single
patient, which causes practical and ethical problems. Another approach is
the use of engineered murine embryonal stem cells, or human cell lines. One
of the best established human cell lines is the embryonal carcinoma cell line
NT2. This cell line is transfectable, capable of differentiating into postmitotic
neuronlike cells (NT2N cells) after treatment with retinoic acid, and transplantable
into the brain or the spinal cord of immunocompetent and immunodeficient rodents.18 Intracerebral grafting of NT2N cells has been used
successfully to promote functional recovery of ischemic rats, and NT2N cells
have been used also as replacement therapy for Parkinson disease. Undifferentiated
human NT2 cells grafted into brains of newborn immunocompetent mice migrate
over distances of several millimeters and differentiate into neuronlike and
oligodendrogliallike cell types.19 These findings
emphasize the usefulness of NT2 cells in therapeutic approaches. The NT2 cells
are particularly valuable, as they may be used as vehicles for the release
of neurotrophic factors into the host brain environment.
Intrauterine transplantation of murine embryonal stem cells into the
brain generated chimeras composed of embryonal stem cell–derived neurons,
oligodendrocytes, and astrocytes.20 These cells
can thus serve also as a valuable source of cell type-specific somatic precursors
for neural transplantation.
Although the field of neural transplantation has been dominated experimentally
and clinically by the transplantation of neuronal cells or their progenitors,
recent glial cell transplantations suggest that such an approach may be on
the verge of therapeutic application in human myelin diseases. As a cell source,
neural stem cells have been exploited as a potential source of oligodendrocyte
precursors.21 These cells can be isolated from
the CNS throughout life and grown as neurospheres by means of conditioned
media. Transplantation of oligodendrocyte precursors into the spinal cords
of rats has shown that these cells can migrate up to 3 to 4 mm from the injection
site, although most of these cells die, mainly by apoptosis. Surviving cells,
however, persist for up to 18 months after transplantation, depending on the
host strain used. It is also possible to promote an oligodendrocytic differentiation
from embryonic stem cells in vitro. Grafting of these cells into rat induces
myelination of axons.20
These advances are promising and suggest that treatment of human neurodegenerative
diseases needs to restore the function of neurons and glial cells. As more
insight is gained into the role of glial cells in brain function, the importance
of these cells in disease processes will become even more apparent. At the
same time, pharmacological and cell transplantation treatments will pay credit
to the therapeutic potential of glial cells.
AUTHOR INFORMATION
Accepted for publication February 11, 2002.
Author contributions: Study concept and design (Drs Kurosinski and Götz); analysis and interpretation
of data (Drs Kurosinski and Götz); drafting
of the manuscript (Dr Götz); critical revision
of the manuscript for important intellectual content (Dr
Kurosinski); obtained funding (Dr Götz);
administrative, technical, and material support (Drs Kurosinski
and Götz); and study supervision (Dr Götz).
This study was supported by grants from the Swiss National Science Foundation,
Berne, and the Bayer Alzheimer Research Network, Wuppertal, Germany (Dr Götz).
Corresponding author and reprints: Jürgen Götz, PhD, Division
of Psychiatry Research, University of Zurich, August Forel Strasse 1, CH-8008
Zürich, Switzerland (e-mail: goetz{at}bli.unizh.ch).
From the Division of Psychiatry Research, University of Zurich, Zurich,
Switzerland.
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