Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3Β pathway in adult rat prefrontal cortex

Dong Xi, Yan Chun Li, Melissa A. Snyder, Ruby Y. Gao, Alicia E. Adelman, Wentong Zhang, Jed S. Shumsky, Wen Jun Gao

Research output: Contribution to journalArticlepeer-review

40 Scopus citations

Abstract

Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of an mGluR2/3 agonist in the MK-801 model of schizophrenia in the rat prefrontal cortex. We found that the mGluR2/3 agonist LY379268 effectively recovered the disrupted expression of NMDA receptors induced by MK-801 administration. This effect was attributable to the direct regulatory action of LY379268 on NMDA receptors via activation of the Akt/GSK-3Β signaling pathway. As occurs with the antipsychotic drug clozapine, acute treatment with LY379268 significantly increased the expression and phosphorylation of NMDA receptors, as well as Akt and GSK-3Β. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3Β inhibitor occluded this effect. In contrast to the widely proposed mechanism of modulating presynaptic glutamate release, our results strongly argue that mGluR2/3 agonists modulate the function of NMDA receptors through postsynaptic actions and reverse the MK-801-induced NMDA dysfunction via the Akt/GSK-3Β pathway. This study provides novel evidence for postsynaptic mechanisms of mGluR2/3 in regulation of NMDA receptors and presents useful insights into the mechanistic actions of mGluR2/3 agonists as potential antipsychotic agents for treating schizophrenia.

Original languageEnglish (US)
Pages (from-to)1260-1274
Number of pages15
JournalNeuropsychopharmacology
Volume36
Issue number6
DOIs
StatePublished - May 2011
Externally publishedYes

Keywords

  • Antipsychotics
  • NMDA antagonism
  • NMDA receptors
  • metabolic glutamate receptors
  • schizophrenia
  • signaling pathway

ASJC Scopus subject areas

  • Pharmacology
  • Psychiatry and Mental health

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