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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.

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.

SUBMITTER: Xi D

PROVIDER: S-EPMC3079418 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature

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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.

Xi Dong D Li Yan-Chun YC Snyder Melissa A MA Gao Ruby Y RY Adelman Alicia E AE Zhang Wentong W Shumsky Jed S JS Gao Wen-Jun WJ

Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology 20110216 6

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 NMD ...[more]

PMID: 21326193

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Project description:BackgroundAbnormal expression of Fanconi anaemia complementation group I (FANCI) has been implicated in carcinogenesis. However, the precise role of FANCI in the development of hepatocellular carcinoma (HCC) remains unclear.Materials & methodsWe conducted a comprehensive bioinformatics analysis of FANCI's role based on HCC patient sequencing data in the TCGA and GEO databases. Then, we performed qPCR, Western blotting (WB), and immunohistochemistry (IHC) assays. SiRNA-mediated knockdown of FANCI was conducted, followed by CCK-8, EdU staining, and colony formation experiments to evaluate the impact of FANCI knockdown on HCC cell behaviour. Flow cytometry was employed to explore alterations in the cell cycle after FANCI knockdown in HCC cell lines. Furthermore, RNA sequencing was performed to investigate potential mechanisms following FANCI knockdown, and WB analysis was used to validate the corresponding pathway.ResultsOur bioinformatics analysis revealed elevated expression of FANCI in HCC, which was subsequently validated through qPCR, WB, and IHC assays. High expression of FANCI was significantly associated with a poor prognosis in HCC patients. Univariate and multivariate Cox regression analyses identified FANCI as an independent prognostic risk factor for HCC patients. Additionally, the coexpressed genes of FANCI were found to be associated with multiple cancer pathways. Knockdown of FANCI expression significantly inhibited HCC cell proliferation and colony formation by inducing cell cycle arrest. Further WB analysis revealed that FANCI knockdown suppressed the expression of Cyclin D1 and p-AKT while increasing the expression of GSK-3β in HCC cells. However, no significant differences were observed in the expression levels of AKT and PI3K.ConclusionOverall, our research provides substantial proof of FANCI's crucial function as an oncogene in HCC. It could serve as a potential prognostic marker, therapeutic target, and tumorigenic factor in HCC.

Dataset Information

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

Publications

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

Similar Datasets

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