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Astrocyte Failure As a Cause of CNS Dysfunction Molecular Psychiatry (2000) 5, 230–232 2000 Macmillan Publishers Ltd All rights reserved 1359-4184/00 $15.00 www.nature.com/mp NEWS & VIEWS Astrocyte failure as a cause of CNS dysfunction All insults to the central nervous systems (CNS), expressing HSV-Tk from the mouse Gfap promoter, including injury, ischemia, infection and degenerative reactive, transgene-expressing astrocytes adjacent to a disease are invariably accompanied by the hypertro- forebrain stab injury are ablated by GCV.8,9 These and phy, altered gene expression and proliferation of astro- other studies have demonstrated the essential nature of cytes, a process commonly referred to as ‘reactive astrocyte functions in a number of contexts related to astrocytosis’. While much is known about molecules the response to injury, and highlighted how astrocyte that either influence, or are produced by, reactive astro- failure might lead to CNS dysfunction in various ways. cytes,1,2 the functions of these cells are incompletely understood. Astrocytes are the most numerous cells in Astrocytes, the blood–brain barrier and interstitial the vertebrate central nervous system (CNS), and vari- edema ous functions have been ascribed to them in the unin- jured CNS, including: provision of structural support The anatomical correlate of the BBB is thought to for neural elements (neuro-glia = neural ‘glue’); homeo- reside in tight junctions between endothelial cells of static maintenance of the extracellular ionic environ- cerebral capillaries, which are of high electrical resist- ment and pH; uptake of extracellular glutamate; regu- ance and present a barrier to charged molecules.10,11 lation of energy metabolism and provision of metabolic Ablation of astrocytes in transgenic mice demonstrates substrates for neurons; axon guidance during develop- an essential role for astrocytes in maintenance and ment; secretion of growth factors and cytokines; and repair of the BBB to protein, and suggests that astrocyte interactions with endothelia to create and maintain the failure can lead to disruption of the BBB.9 Vasogenic blood–brain barrier (BBB).3 The degree to which these brain edema can accompany disruption of the BBB functions are sustained, augmented or lost by astro- with poor outcome in various clinical settings, and has cytes that become reactive after CNS tissue insult is been neuropathologically associated with the pro- only beginning to be determined. Advances in cellular nounced swelling of reactive astrocytes.12 It has not and molecular technology applied to these cells have been known if the astroglial changes contribute to enabled important questions to be addressed regarding development of the edema, and if so, whether edema the roles of astrocytes in the response to insults of vari- is actively triggered by reactive astrocytes, or results ous kinds. These studies highlight the major, and little from a failure of astrocyte functions. Ablation studies recognized, potential for disturbances, or failure, of in trangenic mice support the latter possibility, and astrocyte function to cause dysfunction and pathology suggest that astrocyte failure could in this manner in the CNS. exacerbate a number of CNS disorders.9 Molecular and cellular ablation strategies to study Astrocytes and leukocyte trafficking astrocyte functions In higher vertebrates, leukocytes gain little entry into A number of studies have used gene ablation strategies normal CNS parenchyma, and the CNS inflammatory targeted at molecules specific to astrocytes. These response to injury differs from that of other tissues.13,14 include the gene for glial fibrillary acidic protein After injury, neuronal degeneration or injection of pro- (GFAP), an intermediate filament protein whose inflammatory molecules, blood-borne monocytes and expression in the CNS is restricted to astrocytes and lymphocytes gain delayed and limited access to CNS related cells,4,5 and glutamate transporters specific to parenchyma, whilst polymorphonuclear neutrophils astrocytes.6 In addition, the selective ablation of and mast cells are largely excluded, suggesting that reactive astrocytes has been targeted genetically using the CNS microenvironment contains intrinsic, but the promoter of GFAP linked to the thymidine kinase unknown, anti-inflammatory mechanisms.14–17 After gene of herpes simplex virus (HSV-Tk). Proliferating the ablation of astrocytes in transgenic mice, leuko- cells which express transgene-derived HSV-TK meta- cytes gain increased and prolonged entry into CNS par- bolize the anti-viral agent ganciclovir (GCV) to toxic enchyma adjacent to injury.9 It is not yet clear whether nucleotide analogues which disturb nucleic acid syn- this increased leukocyte entry is a consequence of BBB thesis and induce cell death.7 In transgenic mice disruption or of other factors. Available evidence sug- gests that the tight junctional complexes which form the BBB by restricting the passage of macromolecules Correspondence: MV Sofroniew, Department of Neurobiology and Brain Reseach Institute, UCLA School of Medicine, are not the sole mechanism regulating leukocyte traf- 17 Los Angeles, CA 90095-1763, USA. E-mail: sofroniew@mednet. ficking in the CNS. Mechanisms by which astrocytes ucla.edu could dynamically modulate the entry of leukocytes News & Views 231 into normal or injured CNS parenchyma in addition to, numerous pro- and anti-inflammatory cytokines,1,8 the and perhaps independently of, their influence on the effects of which on neuronal function can be mixed. tight junctional complexes of the BBB include their The importance of astrocyte function for neuropro- ability to produce: (i) both pro- and anti-inflammatory tection is demonstrated by several observations. The cytokines;1,18 and (ii) extracellularly deposited mol- ablation of genes encoding astrocyte-glutamate trans- ecules that positively and negatively influence the porters leads to increased seizurigenesis and gluta- migration of many cell types and nerve fibers.19–21 mate-receptor mediated excitotoxicity.6 CNS injury These findings suggest that dysfunction of astrocyte causes increased levels of extracellular glutamate,28 regulation of leukocyte trafficking in CNS parenchyma and the ablation of astrocytes adjacent to brain injury represents a novel potential pathogenic mechanism for in transgenic mice is associated with pronounced neu- inflammatory disturbances in the CNS. ronal cell death which can be prevented by glutamate- receptor antagonists, indicating that glutamate excito- toxicity contributed to the neuronal death.9 These fin- Astrocytes and CNS myelination dings support and extend other recent evidence that CNS myelination is disturbed in mutant mice in which astrocyte loss or dysfunction represents a potentially astrocyte function has been perturbed by ablation of significant cause of neuronal degeneration.29,30 In the the GFAP gene.4 These findings suggest that astrocytes context of astrocytes’ effects on neuronal function, play an important role in the development and main- mutant mice in which astrocyte function has been per- tenance of CNS myelination. turbed by ablation of the GFAP gene also exhibit some disturbances in neuronal function including induction of LTP and certain types of conditioning.5 Astrocytes and nerve fiber outgrowth, sprouting and regeneration Astrocytes have different effects on nerve fiber growth Conclusions that vary with their states of differentiation.22 Although Together such findings demonstrate the essential nat- CNS astrocytes support neurite outgrowth during ure of astrocyte functions for neuronal health and sur- development and may be important in certain types of vival in the adult CNS. Moreover, astrocyte dysfunc- nerve fiber sprouting in adults,23 evidence accumulated tion may, in addition to influencing neuronal survival for over a century suggests that after CNS injury, or degeneration after CNS insults, have more subtle reactive astrocytes are a major obstacle to the regener- effects on neuronal function that could lead to neu- ation of damaged axons.24 Findings after astrocyte ronal dysfunction at the cellular, systems and ulti- ablation in transgenic mice extend these observations mately behavioral levels, by influencing extracellular by demonstrating that scar-forming astrocytes limit the levels of glutamate or potassium, or through altered growth of nerve fibers after CNS injury in vivo.9 production of cytokines.31 The AIDS-dementia com- plex represents a potential human correlate of astrocyte Astrocytes roles in endogenous neuroprotection dysfunction and failure, where astrocyte infection with 32 and influences on neuronal function human immunodeficiency virus (HIV) may lead not only to production of neurotoxic molecules33 but also A major advance of modern neuroscience has been the to astrocyte failure that could account for at least some recognition that much of the cellular damage resulting of the neuropathological changes and disturbances in from CNS insults is caused by a limited number of neurological function associated with HIV infection of endogenously generated molecules that have poten- the brain,34 as predicted on the basis of cellular and tially neurotoxic activities. Such molecules include molecular ablation studies in experimental animals as glutamate, dopamine, nitric oxide and other transmit- summarized here. ter candidates normally used in intercellular communi- cation, as well as reactive oxygen species generated as MV Sofroniew by-products of metabolism or produced as part of the Department of Neurobiology and Brain inflammatory
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