Glial Cells Under Physiologic and Pathologic Conditions

BASIC SCIENCE SEMINARS IN NEUROLOGY

SECTION EDITOR: HASSAN M. FATHALLAH-SHAYKH, MD Glial Cells Under Physiologic and Pathologic Conditions

Pascal Kurosinski, Dipl Biol; Ju¨rgen Go¨tz, PhD

lial cells have long been considered to play roles in the nervous system that are unex- citing 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, Gneuronlike 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. Arch Neurol. 2002;59:1524-1528

The importance of neurons for central ner- cells that are found in the peripheral nervous system (CNS) function is unques- vous system. In close association with neu- tionable. To assess the potential role of glial rons, astrocytes enwrap synaptic termi- cells, phylogeny may provide a clue. In the nals and make extensive contacts with nematode Caenorhabditis elegans, for ex- endothelial cells from the capillaries. More- ample, a total of 302 neurons but only 56 over, astrocytes are interconnected with glial and supporting cells have been iden- one another by gap junctions. In the den- tified. As one rises through phylogeny, the tate gyrus of the hippocampus, they give ratio of glia to neurons increases, and in rise to new neurons throughout life in humans, the brain contains the highest ra- many vertebrates, including humans.1 tio of glia to neurons (at least 10:1). Con- Historically, glial cells were assigned sequently, one is tempted to suggest that several functions in supporting neurons glial cells play important roles in higher during development and throughout life. cognitive functions. Glial control of the survival of associated Glial and neuronal cells arise from neurons is dependent on prior neuronal progenitors that are initially multipotent triggering of glial cell fate commitment and but gradually become restricted to the neu- trophic factor expression. In addition, glial ronal or glial lineage. Differentiation oc- cells control the migration of neurons dur- curs in a stereotyped sequence whereby ing development. Embryonic neurons are neurons are generated first, followed by typically born at some distance from their glial cells, which differentiate after neu- final sites in the mature nervous system. rogenesis is largely completed. Glial cells The pathways taken by newborn neurons of the CNS can be divided into microglia are specific and depend on cellular con- and macroglia. Microglia are macrophage- tacts and diffusible guidance cues, most of like cells that serve a phagocytic func- which are provided by glial cells and their tion. Macroglia are composed of astro- precursors. Development and lamination cytes and oligodendrocytes, which are the of the mammalian neocortex is con- CNS equivalent of myelinating Schwann trolled by a set of specialized neuroepi- thelial radial glial cells that provide the mi- From the Division of Psychiatry Research, University of Zurich, Zurich, Switzerland. gration scaffold used by roughly 90% of

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 cortical neurons. Several lines of evi- receptors coupled to intracellular cal- ROLE IN MEMORY dence indicate that these radial glia cium mobilization, neuronal activ- AND LEARNING are the precursors of astrocytes in the ity may regulate astrocytic calcium mature brain. An analogous pro- levels.4 Indeed, several laboratories What is the role of glial cells in cess occurs during the migration of have demonstrated that astrocytes memory and learning? Studies in newborn neuronal granule cells in and perisynaptic Schwann cells re- brain slices showed that activation of the cerebellum along Bergmann glial spond to synaptic activity through the astrocytes increased miniature in- processes from the internal granule activation of glial receptors.3 hibitory postsynaptic currents in hip- cell layer of the developing postna- In addition to integration of pocampal pyramidal neurons. Astro- tal cerebellum. neurotransmitter input, astrocytes re- cytes may therefore be necessary in lease their own transmitters that act the activity-dependent modulation of NEURONAL PROPERTIES on neighboring neurons and modu- inhibitory synapses in the hippocam- OF GLIAL CELLS late their function, suggesting a bi- pus.6 A role of astrocytes in synaptic directional signaling pathway be- function is also supported by results Additional, more elaborate func- tween astrocytes and neurons (Figure of studies in mice lacking the inter- tions were recently assigned to glial 1). If glial cells can release neuro- mediate-filament glial fibrillary acidic cells. In the mature nervous sys- transmitters in a regulated manner, protein (GFAP), a protein found pre- tem, examination at the ultrastruc- this process must be a fundamental dominantly in astrocytes of the CNS. tural level reveals a tripartite struc- component of their dialogue with Although astrocytes were present in ture involving the astrocyte that can neurons during synaptic activity. the CNS of the mutant mice, they con- be intimately associated with the A compartmentalization remi- tained a severely reduced number of synapse and that literally enwraps niscent of that of neurons has been intermediate filaments. Since astro- many presynaptic and postsynap- demonstrated for the cerebellar Berg- cytic processes contact synapses and tic terminals2 (Figure 1). This close mann glia. These highly ramified may modulate synaptic function, physical relationship probably pro- glial cells consist of hundreds of in- McCall et al7 examined whether the vides an opportunity for many func- dependent compartments, called mi- hippocampal CA1 region of GFAP- tional interactions between astro- crodomains, that are capable of au- deficient mice was altered in long- cytes and neurons. As an astrocyte tonomous interactions with the term potentiation (the increase in syn- can make contacts with a neuron and particular group of synapses they en- aptic potential after brief high- a capillary, it has the potential to wrap. Stimulation of adjacent par- frequency trains of stimulation). The shuffle nutrients and metabolites be- allel fibers induces localized eleva- mutant mice indeed displayed en- tween the blood supply and the ac- tions of intracellular calcium levels hanced long-term potentiation com- tive neuron (Figure 1). Further- in the Bergmann glia.5 pared with control mice. Therefore, more, as a single astrocyte can make contacts with multiple neurons, Capillary these nonneuronal cells are posi- Glia-Glia Signaling tioned to provide information trans- Through Gap Junction Nutrients fer between neighboring neurons. In the stratum radiatum hippocampi, for example, about 50% of the synapses have astrocytic processes, Transmitter and in 30% of the synapses, an astro- Receptor

cyte process separates 2 neighboring Astrocyte synapses (Figure 1). In addition, astrocytes almost exclusively sur- round synapses that have a high prob- ability of neurotransmitter release. Nutrients Astrocytes express functional receptors for many different neuro- transmitters. Binding to these receptors leads to changes in intracellular calcium levels and even to oscilla- tions in internal calcium levels. Many of the initial studies that demonstrate calcium excitability of astro- Neuron cytes were performed in cell cul- Figure 1. Glial cells under physiologic conditions in the adult brain. Astrocytes make contacts with ture, but studies using acutely neurons and capillaries and shuffle nutrients between the blood supply and the active neuron. As a single isolated brain slices and later acutely astrocyte can make contacts with multiple neurons, these nonneuronal cells are positioned to transfer isolated hippocampi have sup- information between neighboring neurons. Examination at the ultrastructural level (inset) reveals a ported the calcium excitability prop- 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 erty of astrocytes. As astrocytes pos- their own transmitters that act on neighboring neurons. Astrocytes communicate with each other using sess a number of neurotransmitter gap junctions and neurotransmitter-mediated signaling. Adapted in part from Haydon.3

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 Alzheimer Disease Tauopathies cells outnumbered immunoreac- A B tive neurons.12 The glial abnormalities of corticobasal degeneration Amyloid Plaque Disrupted Disrupted Neuro-Glia Glia-Glia include astrocytic plaques and nu- Signaling Signaling Cytotoxicity merous tau-immunoreactive inclusions in the white matter (Table). Neurofibrillary Tangle Although it is likely that the Tau Deposits glial abnormalities affect neuronal Coiled Body Neurons degeneration, it is at present unknown whether they are required for Astrocyte Oligodendrocyte a progression of the disease and its Alexander Disease 10,12 C clinical features. Aspects of the Disrupted Disrupted glial tau abnormalities have been Glia-Glia Neuro-Glia Cytokines Signaling Signaling 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 Rosenthal Fibers expression in oligodendrocytes was much higher than that in neurons. Activated Microglia Reactive Astrocyte Astrocyte Neuron Oligodendroglial G272V tau formed Figure 2. Glial cells under pathologic conditions in the adult brain. A, Reactive astrocytosis as a vigorous filaments and was phosphorylated at response to diverse neurological insults, including viral infections, acute, chronic, and traumatic brain the tau phosphoepitope AT8 that is injuries, and neurodegenerative diseases such as Alzheimer disease (AD). The key histopathological 13 hallmarks of AD, tau-containing neurofibrillary tangles and amyloid plaques, induce astrocytosis and the diagnostic for Alzheimer disease. activation of microglia, which subsequently release cytokines. B, In many tauopathies, tau aggregates are In related transgenic models that numerous in neurons and glial cells. In some brain regions of affected individuals, the glial abnormalities express wild-type or FTDP-17–asso- 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 ciated mutant forms of tau in neu- disease. Eosinophilic deposits of glial fibrillary acidic protein (Rosenthal fibers) are the key pathological rons, the tau abnormalities were re- hallmark of Alexander disease. Again, functional impairment as a consequence of the deposits is likely to stricted to neurons, but microglial affect glia-mediated interactions. and astrocytic cells were activated. In some of these transgenic mouse these mice demonstrate that a pri- plaques and intracellular neurofibril- models, microglia with phagocy- mary defect in astrocytes influences lary tangles that are composed of hy- tosed myelin debris and myelin neuronal physiology.7 In a related perphosphorylated, filamentous mi- ovoids were present, indicating wal- study8 using another GFAP-defi- crotubule-associated tau protein. In lerian degeneration.11 Together, cient mouse strain, excitatory syn- the absence of amyloid plaques, neu- these animal models are useful to aptic transmission from parallel or rofibrillary tangles are also abun- study the pathophysiology and pre- climbing fibers to Purkinje cells was dant in additional neurodegenera- vention of tau filament formation in unaltered in the cerebellum, and these tive diseases, including Pick disease, neurons and glial cells. synapses displayed normal short- progressive supranuclear palsy, cor- The only known late-onset neu- term synaptic plasticity to paired ticobasal degeneration, argyrophilic rodegenerative disease in which glial stimuli. In contrast, long-term de- grain disease, and frontotemporal de- cell inclusions constitute the predomi- pression at parallel-fiber Purkinje cell mentia with parkinsonism linked to nant lesion is multiple system atro- synapses was clearly deficient, sug- chromosome 17 (FTDP-17).9 In con- phy. Clinically, multiple system at- gesting a role for astrocytes in induc- trast to Alzheimer disease, in which rophy includes olivopontocerebellar tion and maintenance of long-term hyperphosphorylated tau protein atrophy, striatonigral degeneration, depression in the cerebellum.8 forms filaments only in neurons, nu- and Shy-Drager syndrome. The cy- merous tau filament–containing glial toplasmic inclusions are strongly im- GLIAL CELLS IN DISEASE cells are present in many of these dis- munoreactive for ␣-synuclein and are eases that are collectively termed found mainly in the cytoplasm and, Results of a recent quantitative post- tauopathies. These disease entities, all to a lesser extent, in the nucleus of oli- mortem investigation of the cere- of which were previously defined as godendrocytes (Table). The forma- bral cortex have convincingly dem- neurodegenerative diseases, are now tion of glial cytoplasmic inclusions onstrated cortical glial cell loss in better considered glianeuronal dis- might be the primary lesion that will patients with major depression. Evi- orders10,11 (Figure 2B). A recent eventually impair nerve cell func- dence is also mounting that glial cell analysis of 2 patients with the disease- tion. Nerve cell loss and clinical symp- loss may be a feature of schizophre- causing FTDP-17–linked tau muta- toms of multiple system atrophy in nia. In addition, glial cells are heavily tion N279K showed widespread neu- the presence of only cytoplasmic in- affected in diseases with cognitive ronal and glial tau accumulation in clusions have been described.14 Physi- dysfunction related to Alzheimer dis- the cortex, basal ganglia, brainstem ologic expression of tau and ␣-synu- ease. Hallmark lesions of Alzheimer nuclei, and white matter. In the neo- clein proteins occur predominantly disease are extracellular amyloid cortex, tau-immunoreactive glial by neurons.

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Disease Affected Cell Type Cell Abnormalities Clinical Syndromes Progressive Astrocytes and Astrocytes: thorn-shaped with tau deposits, Early signs of vertical gaze paresis and supranuclear palsy oligodendrocytes strongly GFAP-positive; oligodendrocytes: progression to total external ophthalmoplegia; coiled bodies with tau inclusions progressive dementia; parkinsonism Corticobasal Astrocytes and Astrocytes: thorn-shaped with tau deposits, Cognitive disturbances, cortical sensory loss, degeneration oligodendrocytes astrocytic plaques positive for tau; extrapyramidal motor dysfunction, and oligodendrocytes: coiled bodies with tau unilateral rigidity inclusions Pick disease Astrocytes and Astrocytes: ramified inclusions and Pick Progressive dementia and personality oligodendrocytes body−like tau inclusions; oligodendrocytes: deterioration, associated with verbal and coiled bodies with tau inclusions are less behavioral stereotypes; extreme form of frequent frontotemporal dementia Alexander disease Astrocytes Contain eosinophilic inclusion bodies called Rare, progressive leukoencephalopathy; infants Rosenthal fibers; cytoplasmic inclusions die within the first decade of life; patients with contain GFAP in association with small heat juvenile or adult forms typically experience shock proteins ataxia, bulbar signs, and spasticity Multiple system atrophy Oligodendrocytes Cytoplasmic and, to a lesser extent, nuclear Orthostatic hypotension, impotence, inclusions of ␣-synuclein incontinence, and parkinsonism; clinically often mistaken for Parkinson disease

*GFAP indicates glial fibrillary acidic protein.

Associated with the accumula- pathological hallmark of all forms of used in grafting protocols have the tion of insoluble protein aggregates Alexander disease is the presence of potential to differentiate into neu- in various disorders, but also with in- Rosenthal fibers, ie, cytoplasmic in- rons and gliallike cells. Cell replace- jury in the nervous system, is the clusions in astrocytes that contain ment therapies are currently used to morphologic activation of astro- GFAP in association with small heat treat Huntington disease or Parkin- cytes and microglial cells, a process shock proteins (Figure 2C). Overex- son disease.16,17 For the latter, clini- called reactive gliosis (Figure 2A). Af- pression of human GFAP in astro- cal trials have been initiated already ter injury, brain macrophages pro- cytes of transgenic mice is fatal and by transplanting human fetal brain liferate and function in tissue re- accompanied by the presence of in- tissue to substitute for the loss of do- pair, including removal of dead tissue clusion bodies indistinguishable from paminergic neurons. However, sev- and debris through phagocytosis. In human Rosenthal fibers. These re- eral aborted fetuses are required for addition, cytokines produced by results suggest that a primary alter- the therapy in a single patient, which active microglia initiate a cascade of ation in the GFAP may be respon- causes practical and ethical prob- cellular responses that greatly influ- sible for Alexander disease. Indeed, lems. Another approach is the use of ence astrocytes. During this pro- results of sequence analysis of DNA engineered murine embryonal stem cess, GFAP is up-regulated in astro- samples from patients representing cells, or human cell lines. One of the cytes. In a variety of conditions, different phenotypes of Alexander best established human cell lines is including injury and neurodegenera- disease showed that most cases are the embryonal carcinoma cell line tive diseases, the GFAP content of as- associated with nonconservative mu- NT2. This cell line is transfectable, trocytes at the site of injury or acti- tations in the coding region of the capable of differentiating into post- vation increases until the astrocyte GFAP. Alexander disease therefore mitotic neuronlike cells (NT2N cells) cell body and its processes are com- represents the first example of a pri- after treatment with retinoic acid, and pletely filled. These reactive astro- mary genetic disorder of astro- transplantable into the brain or the cytes repair damaged brain tissue and cytes.15 spinal cord of immunocompetent and function in the reestablishment of the immunodeficient rodents.18 Intrace- integrity of the microenvironment TRANSPLANTATION rebral grafting of NT2N cells has been surrounding the lesion. APPROACHES TO TREAT used successfully to promote func- In addition to degeneration dur- HUMAN DISEASES tional recovery of ischemic rats, and ing disease and reaction to injury of NT2N cells have been used also as re- the nervous system, glial alterations A common neuropathological fea- placement therapy for Parkinson dis- are the primary cause of the neuro- ture of neurodegenerative diseases is ease. Undifferentiated human NT2 pathological changes in some cases. neuronal cell loss. In addition to cells grafted into brains of newborn Alexander disease is a rare disorder pharmacological treatments, cellu- immunocompetent mice migrate of the CNS of unknown etiology.15 In- lar grafting approaches are cur- over distances of several millime- fants with Alexander disease usu- rently undergoing evaluation for their ters and differentiate into neuron- ally die within the first decade of life; therapeutic potential. These ap- like and oligodendrogliallike cell patients with juvenile or adult forms proaches should appreciate the sub- types.19 These findings emphasize the typically experience ataxia, bulbar stantial cell loss in the glial compart- usefulness of NT2 cells in therapeu- signs, spasticity, and a more slowly ment in many of these diseases, but tic approaches. The NT2 cells are par- progressive course (Table). The also that the cells that are routinely ticularly valuable, as they may be used

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©2002 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/26/2021 as vehicles for the release of neuro- same time, pharmacological and cell 7. McCall MA, Gregg RG, Behringer RR, et al. Tar- trophic factors into the host brain en- transplantation treatments will pay geted deletion in astrocyte intermediate filament (Gfap) alters neuronal physiology. Proc Natl Acad vironment. credit to the therapeutic potential of Sci U S A. 1996;93:6361-6366. Intrauterine transplantation of glial cells. 8. Shibuki K, Gomi H, Chen L, et al. Deficient cer- murine embryonal stem cells into the ebellar long-term depression, impaired eyeblink brain generated chimeras composed Accepted for publication February 11, conditioning, and normal motor coordination in GFAP mutant mice. Neuron. 1996;16:587-599. of embryonal stem cell–derived neu- 2002. 9. Goedert M. Filamentous nerve cell inclusions in rons, oligodendrocytes, and astro- Author contributions: Study neurodegenerative diseases: tauopathies and cytes.20 These cells can thus serve concept and design (Drs Kurosinski ␣-synucleinopathies. Philos Trans R Soc Lond also as a valuable source of cell type- and Go¨ tz); analysis and interpre- B Biol Sci. 1999;354:1101-1118. tation of data (Drs Kurosinski and 10. Komori T. Tau-positive glial inclusions in pro- specific somatic precursors for neu- gressive supranuclear palsy, corticobasal degen- ral transplantation. Go¨tz); drafting of the manuscript (Dr eration and Pick’s disease. Brain Pathol. 1999;9: Although the field of neural Go¨tz); critical revision of the manu- 663-679. transplantation has been dominated script for important intellectual con- 11. Gotz J. Tau and transgenic animal models. Brain experimentally and clinically by the tent (Dr Kurosinski); obtained fund- Res Brain Res Rev. 2001;35:266-286. 12. Delisle MB, Murrell JR, Richardson R, et al. A mu- transplantation of neuronal cells or ing (Dr Go¨ tz); administrative, tation at codon 279 (N279K) in exon 10 of the tau their progenitors, recent glial cell technical, and material support (Drs gene causes a tauopathy with dementia and su- transplantations suggest that such an Kurosinski and Go¨tz); and study supranuclear palsy. Acta Neuropathol (Berl). 1999; approach may be on the verge of pervision (Dr Go¨tz). 98:62-77. This study was supported by 13. Gotz J, Tolnay M, Barmettler R, Chen F, Probst therapeutic application in human my- A, Nitsch RM. Oligodendroglial tau filament for- elin diseases. As a cell source, neu- grants from the Swiss National Sci- mation in transgenic mice expressing G272V tau. ral stem cells have been exploited as ence Foundation, Berne, and the Bayer Eur J Neurosci. 2001;13:2131-2140. a potential source of oligodendro- Alzheimer Research Network, Wup- 14. Goedert M. Alpha-synuclein and neurodegenera- cyte precursors.21 These cells can be pertal, Germany (Dr Go¨tz). tive diseases. Nat Rev Neurosci. 2001;2:492-501. 15. Brenner M, Johnson AB, Boespflug-Tanguy O, Rod- isolated from the CNS throughout life Corresponding author and re- riguez D, Goldman JE, Messing A. Mutations in and grown as neurospheres by means prints: Ju¨rgen Go¨tz, PhD, Division of GFAP, encoding glial fibrillary acidic protein, are of conditioned media. Transplanta- Psychiatry Research, University of associated with Alexander disease. Nat Genet. tion of oligodendrocyte precursors Zurich, August Forel Strasse 1, CH- 2001;27:117-120. 8008 Zu¨ rich, Switzerland (e-mail: 16. Lindvall O, Sawle G, Widner H, et al. Evidence for into the spinal cords of rats has shown long-term survival and function of dopaminergic that these cells can migrate up to 3 [email protected]). grafts in progressive Parkinson’s disease. 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