title: Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex.
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.
authors.affiliation: Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
authors.forename: Dong
authors.initials: D
authors.lastname: Xi
authors.forename: Yan-Chun
authors.initials: YC
authors.lastname: Li
authors.forename: Melissa A
authors.initials: MA
authors.lastname: Snyder
authors.forename: Ruby Y
authors.initials: RY
authors.lastname: Gao
authors.forename: Alicia E
authors.initials: AE
authors.lastname: Adelman
authors.forename: Wentong
authors.initials: W
authors.lastname: Zhang
authors.forename: Jed S
authors.initials: JS
authors.lastname: Shumsky
authors.forename: Wen-Jun
authors.initials: WJ
authors.lastname: Gao
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000633:toxicity; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D051058:Oncogene Protein v-akt / Q000502:physiology*; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000819:agonists* / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology
chemical_list: D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; D016194:Receptors, N-Methyl-D-Aspartate; C108822:metabotropic glutamate receptor 2; D016291:Dizocilpine Maleate; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051058:Oncogene Protein v-akt; D038362:Glycogen Synthase Kinase 3