Role of metabotropic glutamate receptors in oligodendrocyte excitotoxicity and oxidative stress

Wenbin Deng, Hong Wang, Paul A. Rosenberg, Joseph J. Volpe, Frances E. Jensen

Research output: Contribution to journalArticle

137 Scopus citations

Abstract

Developing oligodendrocytes (OLs) are highly vulnerable to excitotoxicity and oxidative stress, both of which are important in the pathogenesis of many brain disorders. OL excitotoxicity is mediated by ionotropic glutamate receptors (iGluRs) of the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/kainate type on these cells. Here we report that metabotropic GluRs (mGluRs) are highly expressed in OL precursors but are down-regulated in mature OLs. Activation of group 1 mGluRs attenuates OL excitotoxicity by controlling downstream oxidative stress after iGluR overactivation and also prevents nonexcitotoxic forms of oxidative stress by inhibiting reactive oxygen species accumulation and intracellular glutathione loss. The modulating effect of group 1 mGluRs on hypoxic-ischemic OL injury is not due to iGluR endocytosis that occurs in neurons in response to mGluR activation but requires activation of PKCα after G protein coupling to phospholipase C. Our results reveal a previously undescribed role for mGluRs in limiting OL injury and suggest that targeting group 1 mGluRs may be a useful therapeutic strategy for treating disorders that involve excitotoxic injury and/or oxidative stress to OLs.

Original languageEnglish (US)
Pages (from-to)7751-7756
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume101
Issue number20
DOIs
StatePublished - May 18 2004
Externally publishedYes

ASJC Scopus subject areas

  • Genetics
  • General

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