α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit composition and cAMP-response element-binding protein regulate oligodendrocyte excitotoxicity

Wenbin Deng, Rachael L. Neve, Paul A. Rosenberg, Joseph J. Volpe, Frances E. Jensen

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Abstract

Developing oligodendrocytes (OLs) are highly vulnerable to glutamate excitotoxicity. Although OL excitotoxicity is mainly mediated by α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors (AMPARs) and is Ca2+-dependent, the molecular basis for AMPAR-mediated Ca2+ influx in OLs remains largely unclear. Ca 2+ permeability of AMPARs is inversely correlated with the abundance of the AMPAR subunit glutamate receptor 2 (GluR2). Here we report that GluR2-containing and GluR2-lacking AMPARs are co-expressed in individual OLs and that a subset of AMPARs on each OL are Ca2+-permeable and mediate OL excitotoxicity. Virus-mediated overexpression of GluR2 reduces OL excitotoxicity, whereas expression of its unedited form GluR2(Q) enhances the excitotoxicity. These findings indicate that GluR2 critically controls OL excitotoxicity. During OL excitotoxicity, the transcriptional factor cAMP-response element-binding protein (CREB) is transiently phosphorylated and subsequently down-regulated. Virus-mediated expression of a constitutively active form of CREB, both in cultured OLs in vitro and in developing cerebral white matter in vivo, up-regulates GluR2, inhibits Ca2+ permeability, and protects OLs from excitotoxicity. Overall, these data suggest that targeting GluR2-lacking AMPARs or CREB may be a useful strategy for treating nervous system disorders associated with OL excitotoxicity.

Original languageEnglish (US)
Pages (from-to)36004-36011
Number of pages8
JournalJournal of Biological Chemistry
Volume281
Issue number47
DOIs
StatePublished - Nov 24 2006

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Isoxazoles
Cyclic AMP Response Element-Binding Protein
Oligodendroglia
Propionates
Glutamate Receptors
AMPA Receptors
Chemical analysis
Viruses
Permeability
Neurology
Glutamic Acid
Nervous System Diseases

ASJC Scopus subject areas

  • Biochemistry

Cite this

α-amino-3-hydroxy-5-methyl-4-isoxazole propionate receptor subunit composition and cAMP-response element-binding protein regulate oligodendrocyte excitotoxicity. / Deng, Wenbin; Neve, Rachael L.; Rosenberg, Paul A.; Volpe, Joseph J.; Jensen, Frances E.

In: Journal of Biological Chemistry, Vol. 281, No. 47, 24.11.2006, p. 36004-36011.

Research output: Contribution to journalArticle

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