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Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity

Abstract

Little is known of the molecular mechanisms that trigger oligodendrocyte death and demyelination in many acute central nervous system insults. Since oligodendrocytes express functional α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)/kainate-type glutamate receptors, we examined the possibility that oligodendrocyte death can be mediated by glutamate receptor overactivation. Oligodendrocytes in primary cultures from mouse forebrain were selectively killed by low concentrations of AM PA, kainate or glutamate, or by deprivation of oxygen and glucose. This toxicity could be blocked by the AMPA/kainate receptor antagonist 6-nitro-7-sulfamoylbenzo(f)quinoxaline-2,3-dione (NBQX). In vivo, differentiated oligodendrocytes in subcortical white matter expressed AMPA receptors and were selectively injured by microstereotaxic injection of AMPA but not NMDA. These data suggest that oligodendrocytes share with neurons a high vulnerability to AMPA/kainate receptor-mediated death, a mechanism that may contribute to white matter injury in CNS disease.

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References

  1. Bunge, R.P. et al. Observations on the pathology of human spinal cord injury: A review and classification of 22 new cases with details from a case of chronic cord compression with extensive focal demyelination. in Advances in Neurology (ed. Seil, F.J.) 59, 75–89 (Raven Press, New York, 1993).

  2. Gledhill, R.F., Harrison, B.M. & McDonald, W.I. Demyelination after acute spinal cord compression. Exp. Neurol. 38, 472–487 (1973).

    Article  CAS  PubMed  Google Scholar 

  3. Hirano, A., Levine, S. & Zimmerman, H.M. Experimental cyanide encephalopathy: Electron microscopic observations of early lesions in white matter. J. Neuropathol. Exp. Neurol. 26, 200–21 3 (1967).

    Article  CAS  PubMed  Google Scholar 

  4. Okeda, R. et al. The pathogenesis of carbon monoxide encephalopathy in the acute phase—physiological and morphological correlation. Acta Neuropathol. 54, 1–10 (1981).

    Article  CAS  PubMed  Google Scholar 

  5. Fisher, CM. Lacunes: Small, deep cerebral infarcts. Neurology 15, 774–784 (1965).

    Article  CAS  PubMed  Google Scholar 

  6. Plum, F., Posner, J.B. & Hain, R.F. Delayed neurological deterioration after anoxia. Arch. Intern. Med. 110, 56–63 (1962).

    Article  Google Scholar 

  7. Ginsberg, M.D. Delayed neurological deterioration following hypoxia. in Advances in Neurology (ed. Fahn, S.) 26, 21–45 (Raven Press, New York, 1979).

    Google Scholar 

  8. Banker, B.Q. & larroche, J.-C. Periventricular leukomalacia of infancy. Arch. Neurol. 7, 32–56 (1962).

    Article  Google Scholar 

  9. Rivkin, M.J. & Volpe, J.J. Hypoxic-ischemic brain injury in the newborn. Semin. Neurol. 13, 30–90 (1993).

    Article  CAS  PubMed  Google Scholar 

  10. Pantoni, L., Garcia, J.H. & Gutierrez, J.A. Cerebral white matter is highly vulnerable to ischemia. Stroke 27, 1641–1647 (1996).

    Article  CAS  PubMed  Google Scholar 

  11. Raine, C.S., The Norton Lecture: A review of the oligodendrocyte in the multiple sclerosis lesion. J. Neuroimmunol. 77, 135–152 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Benveniste, H., Drejer, J., Schousboe, A. & Diemer, N.H. Elevation of the extracellular concentrations of glutamate and aspartate in rat hippocampus during transient cerebral ischemia monitored by intracerebral dialysis. J. Neurochem. 43, 1369–1374 (1984).

    Article  CAS  PubMed  Google Scholar 

  13. Rothman, S.M. & Olney, J.W. Excitotoxicity and the NMDA receptor. Trends Neurosci. 10, 299 (1987).

    Article  CAS  Google Scholar 

  14. Choi, D.W. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1, 623 (1988).

    Article  CAS  PubMed  Google Scholar 

  15. Steinhauser, C. & Gallo, V. News on glutamate receptors in glial cells. Trends Neurosci. 19, 339–345 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Holtzclaw, L.A., Gallo, V., Russell, J.T. AMPA receptors shape Ca2+ responses in cortical oligodendrocyte progenitors and CG-4 cells. J. Neurosci. Res. 42, 124–130 (1995).

    Article  CAS  PubMed  Google Scholar 

  17. David, J.C. et. al. AMPA receptor activation is rapidly toxic to cortical astrocytes when desensitization is blocked. J. Neurosci. 16, 200–209 (1995).

    Article  Google Scholar 

  18. Yamada, K.A. & Rothman, S.M. Diazoxide blocks glutamate desensitization and prolongs excitatory postsynaptic currents in rat hippocampal neurons. J. Physiol. (Lond.) 458, 409–423 (1992).

    Article  CAS  Google Scholar 

  19. Patneau, D.K., Vyklicky, L. & Mayer, M.L. Hippocampal neurons exhibit cycloth-iazide-sensitive rapidly desensitizing responses to kainate. J. Neurosci. 13, 3496–3509 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yoshioka, A. et al. α-Amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors mediate excitotoxicity in the oligodendroglial lineage. Neurochemistry 64, 2442–2448 (1995).

    Article  CAS  Google Scholar 

  21. Oka, A., Belliveau, M.J., Rosenberg, P.A. & Volpe, J.J. Vulnerability of oligoden-droglia to glutamate: Pharmacology, mechanisms, and prevention. J. Neurosci. 13, 1441–1453 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Choi, D.W., Maulucci-Gedde, M. & Kriegstein, R. Glutamate neurotoxicity in cortical cell culture. J. Neurosci. 7, 357–368 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Frandsen, A. & Schousboe, A. Development of excitatory amino acid induced cyto-toxicity in cultured neurons. Int. J. Dew. Neurosci. 8, 209–216 (1990).

    Article  CAS  Google Scholar 

  24. Zhong, J. et al. Expression of mRNAs encoding subunits of the N-methyl-D-aspartate receptor in cultured cortical neurons. Mol. Pharmacol. 45, 846–853 (1994).

    CAS  PubMed  Google Scholar 

  25. Wahl, P., Honore, T., Drejer, J. & Schousboe, A. Development of binding sites for excitatory amino acids in cultured cerebral cortex neurons. Int. J. Dev. Neurosci. 9, 287–296 (1991).

    Article  CAS  PubMed  Google Scholar 

  26. McDonald, J.W. & Johnston, M.V. Physiological and pathophysiological roles of excitatory amino acids during central nervous system development. Brain Res. Rev. 15, 41–70 (1990).

    Article  PubMed  Google Scholar 

  27. McCarthy, K.D. & de Vellis, J. Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J. Cell Biol. 85, 890–902 (1980).

    Article  CAS  PubMed  Google Scholar 

  28. Barres, B.A. et al. Cell death and control of cell survival in the oligodendrocyte lineage. Cell 70, 31–46 (1992).

    Article  CAS  PubMed  Google Scholar 

  29. Ishii, S. & Volpe, J.J. Establishment of a culture system for the study of oligodendroglial development: Complementary effects of boiled serum and astrocyte extract. Dev. Neurosci. 14, 230–237 (1992).

    Article  CAS  PubMed  Google Scholar 

  30. Barres, B.A., Schmid, R., Sendnter, M. & Raff, M.C. Multiple extracellular signals are required for long-term oligodendrocyte survival. Development 118, 283–295 (1993).

    CAS  PubMed  Google Scholar 

  31. Oh, L.Y. & Yong, V.W. Astrocytes promote process outgrowth by adult human oligodendrocytes in vitro through the interaction between bFGF and astrocyte extracellular matrix. Glia 17, 237–253 (1996).

    Article  CAS  PubMed  Google Scholar 

  32. McDonald, J.W. et al. Cyclosporine induces neuronal apoptosis and selective oligodendrocyte death in cortical cultures. Ann. Neurol. 40, 750–758 (1996).

    Article  CAS  PubMed  Google Scholar 

  33. Wolswijk, G. & Noble, M. Identification of an adult-specific glial progenitor cell. Development 105, 387–400 (1989).

    CAS  PubMed  Google Scholar 

  34. Miller, R.H. Oligodendrocyte origins. Trends Neurosci. 19, 92–96 (1996).

    Article  CAS  PubMed  Google Scholar 

  35. Petralia, R.S. & Wenthold, R.J. Light and electron immunocytochemical localization of AMPA-selective glutamate receptors in the rat brain. J. Comp. Neurol. 318, 329–354(1992).

    Article  CAS  PubMed  Google Scholar 

  36. Grynkiewicz, G., Poenie, M. & Tsien, R. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J. Biol. Chem. 260, 3440–3450 (1985).

    CAS  PubMed  Google Scholar 

  37. Louis, J.C., Magal, E., Takayama, S. & Varon, S. CNTF protection of oligodendrocytes against natural and tumor necrosis factor-induced death. Science 259, 689–692(1993).

    Article  CAS  PubMed  Google Scholar 

  38. D'Souza, S.D., Alinauskas, K.A. & Antel, J.P. Ciliary neurotrophic factor selectively protects human oligodendrocytes from tumor necrosis factor-mediated injury. J. Neurosci. Res. 43, 289–298 (1996).

    Article  CAS  PubMed  Google Scholar 

  39. Noble, M. & Mayer-Proschel, M. On the track of cell survival Pharmaceuticals in the oligodendrocyte type-2 lineage. Perspect Dev. Neurobiol. 3, 121–131 (1996).

    CAS  PubMed  Google Scholar 

  40. Kahn, M.A. & De Vellis, J. Regulation of an oligodendrocyte progenitor cell line by the interleukin-6 family of cytokines. Glia 12, 87–98 (1994).

    Article  CAS  PubMed  Google Scholar 

  41. Rosenberg, P.A., Amin, S. & Leitner, M. Glutamate uptake disguises neurotoxic potency of glutamate agonists in cerebral cortex in dissociated cell culture. J. Neurosci. 12, 56–61 (1992).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Bridges, R.J. et al. Conformationally defined neurotransmitter analogues. Selective inhibition of glutamate uptake by one pyrrolidine-2,4-dicarboxylate diastereomer. J. Med. Chem. 34, 717–725 (1991).

    Article  CAS  PubMed  Google Scholar 

  43. Goldberg, M.P. & Choi, D.W. Combined oxygen and glucose deprivation in cortical cell culture: Calcium-dependent and calcium-independent mechanisms of neuronal injury. J. Neurosci. 13, 3510–3524 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Friedman, B. et al. In situ demonstration of mature oligodendrocytes and their processes: An immunocytochemical study with a new monoclonal antibody, Rip. Glia 2, 380–390 (1989).

    Article  CAS  PubMed  Google Scholar 

  45. Koh, J.Y., Goldberg, M.P., Hartley, D.M. & Choi, D.W. Non-NMDA receptor-mediated neurotoxicity in cortical culture. J. Neurosci. 10, 693–705 (1990).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Kaku, D.A., Goldberg, M.P. & Choi, D.W. Antagonism of non-NMDA receptors augments the neuroprotective effect of NMDA receptor blockade in cortical cultures subjected to prolonged deprivation of oxygen and glucose. Brain Res. 554, 344–347(1991).

    Article  CAS  PubMed  Google Scholar 

  47. Ratan, R.R., Murphy, T.H. & Baraban, J.M. Oxidative stress induces apoptosis in embryonic cortical neurons. J. Neurochem. 62, 37–379 (1994).

    Google Scholar 

  48. McDonald et al. Susceptibility to apoptosis is enhanced in immature cortical neurons. Brain Res. 759, 228–232 (1997).

    Article  CAS  PubMed  Google Scholar 

  49. Yoshioka, A., Bacskai, B. & Pleasure, D. Pathophysiology of oligodendroglial excitotoxicity. J. Neurosci. Res. 46, 427–437 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Kerr, J.F.R., Wyllie, A.H. & Currie, A.R. Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics, fir. J. Cancer 26, 239–257 (1972).

    Article  CAS  Google Scholar 

  51. Bonfoco, E. et al. Apoptosis and necrosis: Two distinct events induced, respectively, by mild and intense insults with N-methyl-D-aspartate or nitric oxide/superoxide in cortical cell cultures. Proc. Natl. Acad. Sci. USA 92, 7162–7166 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Gwag, B.J. et al. Blockade of glutamate receptors unmasks neuronal apoptosis after oxygen-glucose deprivation in vitro. Neuroscience 68, 615–619 (1995).

    Article  CAS  PubMed  Google Scholar 

  53. Coyle, J.T., Molliver, M.E. & Kuhar, M.J. In situ injection of kainic acid: A new method for selectively lesioning neuronal cell bodies while sparing axons of passage. J. Comp. Neurol. 180, 301–324 (1978).

    Article  CAS  PubMed  Google Scholar 

  54. Dusart, I., Marty, S. & Peschanski, M., Demyelination and ination, and remyelination by Schwann cells and oligodendrocytes after kainate-induced neuronal depletion in the central nervous system. Neuroscience 51, 137–148 (1992).

    Article  CAS  PubMed  Google Scholar 

  55. Zaczek, R., Simonton, S. & Coyle, J.T. Local and distant neuronal degeneration following intrastriatal injection of kainic acid. J. Neuropathol. Exp. Neurol. 39, 245–264 (1980).

    Article  CAS  PubMed  Google Scholar 

  56. Waxman, S.G. Conduction in myelinated, unmyelinated, and demyelinated fibers. Arch. Neurol. 34, 585–598 (1977).

    Article  CAS  PubMed  Google Scholar 

  57. Sheardown, M.J., Suzdak, P.D. & Nordholm, L. AMPA, but not NMDA, receptor antagonism is neuroprotective in gerbil global ischaemia, even when delayed 24h. Eur. J. Pharmacol. 236, 347–353 (1993).

    Article  CAS  PubMed  Google Scholar 

  58. Wrathall, J.R., Bouzoukis, J. & Choiniere, D. Effect of kynurenate on functional deficits resulting from traumatic spinal cord injury. Eur. J. Pharm. 218, 273–281 (1992).

    Article  CAS  Google Scholar 

  59. Wrathall, J.R., Choiniere, D. & Teng, Y.D. Dose-dependent reduction of tissue loss and functional impairment after spinal cord trauma with the AMPA/kainate antagonist NBQX. J. Neurosci. 14, 6598–6607 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Matute, C., Sanchez-Gomez, M.V., Martinez-Millan, L. & Miledi, R. Glutamate receptor-mediated toxicity in optic nerve oligodendrocytes. Proc. Natl. Acad. Sci. 94, 8830–8835 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Mcdonald, J., Althomsons, S., Hyrc, K. et al. Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity. Nat Med 4, 291–297 (1998). https://doi.org/10.1038/nm0398-291

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