Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • News and Commentary
  • Published:

News & Commentary

Astrocyte failure as a cause of CNS dysfunction

Molecular Psychiatry volume 5, pages 230–232 (2000)Cite this article

All insults to the central nervous systems (CNS), including injury, ischemia, infection and degenerative disease are invariably accompanied by the hypertrophy, altered gene expression and proliferation of astrocytes, a process commonly referred to as ‘reactive astrocytosis’. While much is known about molecules that either influence, or are produced by, reactive astrocytes,1, 2 the functions of these cells are incompletely understood. Astrocytes are the most numerous cells in the vertebrate central nervous system (CNS), and various functions have been ascribed to them in the uninjured CNS, including: provision of structural support for neural elements (neuro-glia = neural ‘glue’); homeostatic maintenance of the extracellular ionic environment and pH; uptake of extracellular glutamate; regulation of energy metabolism and provision of metabolic substrates for neurons; axon guidance during development; secretion of growth factors and cytokines; and interactions with endothelia to create and maintain the blood–brain barrier (BBB).3 The degree to which these functions are sustained, augmented or lost by astrocytes that become reactive after CNS tissue insult is only beginning to be determined. Advances in cellular and molecular technology applied to these cells have enabled important questions to be addressed regarding the roles of astrocytes in the response to insults of various kinds. These studies highlight the major, and little recognized, potential for disturbances, or failure, of astrocyte function to cause dysfunction and pathology in the CNS.

A number of studies have used gene ablation strategies targeted at molecules specific to astrocytes. These include the gene for glial fibrillary acidic protein (GFAP), an intermediate filament protein whose expression in the CNS is restricted to astrocytes and related cells,4, 5 and glutamate transporters specific to astrocytes.6 In addition, the selective ablation of reactive astrocytes has been targeted genetically using the promoter of GFAP linked to the thymidine kinase gene of herpes simplex virus (HSV-Tk). Proliferating cells which express transgene-derived HSV-TK metabolize the anti-viral agent ganciclovir (GCV) to toxic nucleotide analogues which disturb nucleic acid synthesis and induce cell death.7 In transgenic mice expressing HSV-Tk from the mouse Gfap promoter, reactive, transgene-expressing astrocytes adjacent to a forebrain stab injury are ablated by GCV.8, 9 These and other studies have demonstrated the essential nature of astrocyte functions in a number of contexts related to the response to injury, and highlighted how astrocyte failure might lead to CNS dysfunction in various ways.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

References

  1. Eddleston M, Mucke L . Molecular profile of reactive astrocytes—implications for their role in neurological disease Neuroscience 1993; 54: 15–36

    Article  CAS  Google Scholar 

  2. Ridet JL, Malhotra SK, Privat A, Gage FH . Reactive astrocytes: cellular and molecular cues to biological function Trends Neurosci 1997; 20: 570–577

    Article  CAS  Google Scholar 

  3. Kettenmann H, Ransom BR (eds) . Neuroglia Oxford University Press: New York 1995

    Google Scholar 

  4. Liedtke W, Edelmann W, Bieri PL, Chiu F, Cowan NJ, Kucherlapati R et al. GFAP is necessary for the integrity of CNS white matter architecture and long-term maintenance of myelination Neuron 1996; 17: 607–615

    Article  CAS  Google Scholar 

  5. Shibuki K, Gomi H, Chen L, Bao S, Kim JJ, Wakatsuki H et al. Deficient cerebellar long-term depression, impaired eyeblink conditioning, and normal motor coordination in GFAP mutant mice Neuron 1996; 16: 587–599

    Article  CAS  Google Scholar 

  6. Rothstein JD, Dykes-Hoberg M, Pardo CA, Bristol LA, Jin L, Kunci RW et al. Knockout of glutamate transporters reveals a major role for astroglial transport in excitotoxicity and clearance of glutamate Neuron 1996; 16: 675–686

    Article  CAS  Google Scholar 

  7. Borrelli E, Heyman R, Hsi M, Evans RM . Targeting of an inducible toxic phenotype in animal cells Proc Natl Acad Sci USA 1988; 85: 7572–7576

    Article  CAS  Google Scholar 

  8. Bush TG, Savidge TC, Freeman TC, Cox HJ, Campbell EA, Mucke L et al. Fulminant jejuno-ileitis following ablation of enteric glia in adult transgenic mice Cell 1998; 93: 189–201

    Article  CAS  Google Scholar 

  9. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN et al. Leukocyte infiltration, neuronal degeneration and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice Neuron 1999; 23: 297–308

    Article  CAS  Google Scholar 

  10. Brightman MW, Reese TS . Junctions between intimately apposed cell membranes in the vertebrate brain J Cell Biol 1969; 40: 648–677

    Article  CAS  Google Scholar 

  11. Rubbin LL, Staddon JM . The cell biology of the blood–brain barrier Ann Rev Neurosci 1999; 22: 11–28

    Article  Google Scholar 

  12. Klatzo I . Neuropathological aspects of brain edema J Neuropathol Exp Neurol 1967; 26: 1–13

    Article  CAS  Google Scholar 

  13. Dowding AJ, Scholes J . Lymphocytes and macrophages outnumber oligodendroglia in normal fish spinal cord Proc Natl Acad Sci USA 1993; 90: 10183–10187

    Article  CAS  Google Scholar 

  14. Perry VH, Andersson PB, Gordon S . Macrophages and inflammation in the central nervous system Trends Neurosci 1993; 16: 268–273

    Article  CAS  Google Scholar 

  15. Hirschberg DL, Schwartz M . Macrophage recruitment to acutely injured central nervous system is inhibited by a resident factor: a basis for an immune-brain barrier J Neuroimmunol 1995; 61: 89–96

    Article  CAS  Google Scholar 

  16. Raivich G, Jones LL, Kloss CUA, Werner A, Neumann H, Kreutzberg GW . Immune surveillance in the injured nervous system: T-lymphocytes invade the axotomized mouse facial motor nucleus and aggregate around sites of neuronal degeneration J Neurosci 1998; 18: 5804–5816

    Article  CAS  Google Scholar 

  17. Carson MJ, Sutcliffe JG . Balancing function vs. self defense: the CNS as an active regulator of immune responses J Neurosci Res 1999; 55: 1–8

    Article  CAS  Google Scholar 

  18. Ransohoff RM, Tani M . Do chemokines mediate leukocyte recruitment in post-traumatic CNS inflammation? Trends Neurosci 1998; 21: 154–159

    Article  CAS  Google Scholar 

  19. Blakemore WF, Crang AJ . The relationship between type-1 astrocytes, Schwann cells and oligodendrocytes following transplantation of glial cell cultures into demyelinating lesions in the adult rat spinal cord J Neurocytol 1989; 18: 519–528

    Article  CAS  Google Scholar 

  20. Grumet M, Flaccus A, Margolis RU . Functional characterization of chondroitin sulfate proteoglycans of brain: interactions with neurons and neural cell adhesion molecules J Cell Biol 1993; 120: 815–824

    Article  CAS  Google Scholar 

  21. Davies SJA, Fitch MT, Memberg SP, Hall AK, Raisman G, Silver J . Regeneration of adult axons in white matter tracts of the central nervous system Nature 1997; 390: 680–683

    Article  CAS  Google Scholar 

  22. Hatten ME, Liem RKH, Shwlanski ML, Mason SA . Astroglia in CNS injury Glia 1991; 4: 233–243

    Article  CAS  Google Scholar 

  23. Gage FH, Olejniczak P, Armstrong DM . Astrocytes are important for sprouting in the septohippocampal circuit Exp Neurol 1988; 102: 2–13

    Article  CAS  Google Scholar 

  24. Ramon y Cajal S . Degeneration and Regeneration of the Nervous System Oxford University Press: London 1928

    Google Scholar 

  25. Rothstein JD, Martin L, Levey AI, Dykes-Hoberg M, Jin L, Wu D et al. Localization of neuronal and glial glutamate transporters Neuron 1994; 13: 713–725

    Article  CAS  Google Scholar 

  26. Wilson JX . Antioxidant defense of the brain: a role for astrocytes Can J Physiol Pharmacol 1997; 75: 1149–1163

    Article  CAS  Google Scholar 

  27. Sofroniew MV, Mobley WC . Nerve growth factor, neuroprotection and neural repair Ann Rev Neurosci 2001; 24:: (in press)

  28. Faden AI, Demediuk P, Panter SS, Vink R . The role of excitatory amino acids and NMDA receptors in traumatic brain injury Science 1989; 244: 798–800

    Article  CAS  Google Scholar 

  29. Budd SL, Lipton SA . Calcium tsunamis: do astrocytes transmit cell death messages via gap junctions during ischemia? Nature Neurosci 1998; 1: 431–432

    Article  CAS  Google Scholar 

  30. Lin JH-C, Weigel H, Cotrina ML, Liu S, Bueno E, Hansen AJ et al. Gap-junction-mediated propagation and amplification of cell injury Nature Neurosci 1998; 1: 494–500

    Article  CAS  Google Scholar 

  31. Licinio J, Wong ML . The role of inflammatory mediators in the biology of major depression: central nervous system cytokines modulate the biological substrate of depressive symptoms, regulate stress-responsive systems, and contribute to neurotoxicity and neuroprotection Mol Psychiatry 1999; 4: 317–327

    Article  CAS  Google Scholar 

  32. Fiala M, Rhodes RH, Shapsak P, Nagano I, Martinez-Maza O, Diagne A et al. Regulation of HIV-1 infection in astrocytes: expression of Nef, TNF-α and IL-6 is enhanced in coculture of astrocytes and macrophages J Neurovirol 1996; 2: 158–166

    Article  CAS  Google Scholar 

  33. Toggas SM, Masliah E, Rockenstein EM, Rall GF, Abraham CR, Mucke L . Central nervous system damage produced by expression of the HIV-1 coat protein gp120 in transgenic mice Nature 1994; 367: 188–193

    Article  CAS  Google Scholar 

  34. Glass JD, Johnson RT . Human immunodeficiency virus and the brain Ann Rev Neurosci 1966; 19: 1–26

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Neurobiology and Brain Research Institute, UCLA School of Medicine, Los Angeles, 90095-1763, CA, USA

    M V Sofroniew

Authors
  1. M V Sofroniew
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M V Sofroniew.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sofroniew, M. Astrocyte failure as a cause of CNS dysfunction. Mol Psychiatry 5, 230–232 (2000). https://doi.org/10.1038/sj.mp.4000753

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.mp.4000753

This article is cited by

Search

Advanced search

Quick links