Pathophysiology of oligodendroglial excitotoxicity

Akira Yoshioka, Brian Bacskai, David E Pleasure

Research output: Contribution to journalArticle

118 Scopus citations

Abstract

Oligodendrocyte-like cells (OLD) derived from the rat oligodendroglial precursor line, CG-4, express Ca2+-permeable non-methyl-D-aspartate glutamate receptor channels (GluR). Exposure to kainate, an L-glutamate analogue, markedly elevates OLC Ca2+ influx and cytosolic [Ca2+], and results in damage to both OLC plasma membrane and OLC nuclear DNA. Two observations indicate that kainate-induced OLC internucleosomal DNA nicking is not simply a delayed consequence of cell necrosis: 1) there is no temporal lag between onset of plasma membrane injury and of DNA nicking; and 2) aurintricarboxylic acid, an endonuclease inhibitor, blocks kainate-induced damage to the plasma membrane. N-acetyl-L-cysteine also inhibits OLC kainate injury, suggesting that reactive oxygen species participate in OLC excitotoxicity. Kainate-induced OLC Ca2+ influx and excitotoxicity are blocked by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), indicating that these kainate effects are mediated by AMPA-GluR. AMPA and L- glutamate fail to elicit OLC damage unless cyclothiazide, an AMPA-GluR desensitization blocker, is present. OLC express both the 'flip' and 'flop' forms of GluR2, GluR3, and GluR4 mRNAs, but neither flip nor flop GluR1 mRNA. These data, together with the restriction of the desensitization-blocking activity of cyclothiazide to GluR containing flip-encoded GluR subunits, and the sharply diminished Ca2+ permeability of GluR containing edited GluR2, suggest OLC excitotoxicity is mediated by AMPA-GluR that contain flip GluR3 and/or flip GluR4 protein subunits, but neither flip nor flop GluR2 protein subunits. Rapid desensitization of these GluR is likely to be important in protecting cells of the oligodendroglial lineage from excitotoxicity.

Original languageEnglish (US)
Pages (from-to)427-437
Number of pages11
JournalJournal of Neuroscience Research
Volume46
Issue number4
DOIs
StatePublished - 1996
Externally publishedYes

Keywords

  • apoptosis
  • cyclothiazide
  • excitotoxicity
  • glutamate receptor
  • kainate
  • oligodendroglia
  • receptor desensitization

ASJC Scopus subject areas

  • Neuroscience(all)

Fingerprint Dive into the research topics of 'Pathophysiology of oligodendroglial excitotoxicity'. Together they form a unique fingerprint.

  • Cite this