Journal
NEUROPSYCHOPHARMACOLOGY
Volume 36, Issue 6, Pages 1260-1274Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/npp.2011.12
Keywords
Antipsychotics; metabolic glutamate receptors; NMDA receptors; NMDA antagonism; signaling pathway; schizophrenia
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Funding
- NARSAD (National Alliance for Research on Schizophrenia and Depression)
- NIH [R21 MH232307, R01 MH232395]
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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-3b 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-3b. Physiologically, LY379268 significantly enhanced NMDA-induced current in prefrontal neurons and a GSK-3b 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-3b 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. Neuropsychopharmacology (2011) 36, 1260-1274; doi: 10.1038/npp.2011.12; published online 16 February 2011
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