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Group II Metabotropic Glutamate Receptor Agonist Ameliorates MK801-Induced Dysfunction of NMDA Receptors via the Akt/GSK-3β Pathway in Adult Rat Prefrontal Cortex
Journal article   Open access   Peer reviewed

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 and Wen-Jun Gao
Neuropsychopharmacology (New York, N.Y.), v 36(6), pp 1260-1274
May 2011
DOI: https://doi.org/10.1038/npp.2011.12
PMID: 21326193
Featured in Collection :   UN Sustainable Development Goals @ Drexel
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https://doi.org/10.1038/npp.2011.12View
Published, Version of Record (VoR) Open

Abstract

Antipsychotics animal models metabolic glutamate receptors signal transduction signaling pathway NMDA antagonism schizophrenia NMDA receptors NMDA receptor Original glutamate mGluR agonist
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-3 β 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-3 β . Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3 β 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-3 β 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.

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Domestic collaboration
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Web of Science research areas
Neurosciences
Pharmacology & Pharmacy
Psychiatry
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