Oligodendrocytes from forebrain are highly vulnerable to AMPA/kainate receptor-mediated excitotoxicity.
Little is known of the molecular mechanisms that trigger oligodendrocyte death and demyelination in many acute central nervous system insults. Since oligodendrocytes express functional alpha-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 AMPA, 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.
McDonald
J W
JW
Center for the Study of Nervous System Injury and Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Althomsons
S P
SP
Hyrc
K L
KL
Choi
D W
DW
Goldberg
M P
MP
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002545:Brain Ischemia / Q000378:metabolism / Q000473:pathology; D016923:Cell Death; D002478:Cells, Cultured; D018698:Glutamic Acid / Q000633:toxicity; D006133:Growth Substances / Q000494:pharmacology; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D008297:Male; D051379:Mice; D008845:Microinjections; D009836:Oligodendroglia / Q000378:metabolism / Q000473:pathology*; D016548:Prosencephalon / Q000187:drug effects / Q000473:pathology*; D051381:Rats; D011919:Rats, Inbred Strains; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018092:Kainic Acid Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000633:toxicity
D000975:Antioxidants; D018698:Glutamic Acid; D006133:Growth Substances; D007608:Kainic Acid; D018091:Receptors, AMPA; D018092:Kainic Acid Receptors; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid