Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex.
Group II metabotropic glutamate receptor agonist ameliorates MK801-induced dysfunction of NMDA receptors via the Akt/GSK-3β pathway in adult rat prefrontal cortex.
复制标题
DOI：
10.1038/npp.2011.12
复制
发表时间：
2011-05
期刊：
影响因子：
--
通讯作者：
中科院分区：
文献类型：
--
作者：
针对mGluRs的药物干预已成为精神分裂症的潜在治疗方法，而所涉及的机制仍然难以捉摸。我们探讨了mGluR 2/3激动剂在MK-801精神分裂症模型大鼠前额叶皮层中的抗精神病作用。我们发现，mGluR 2/3激动剂LY 379268有效地恢复了由MK-801给药诱导的NMDA受体表达的破坏。该作用归因于LY 379268通过激活Akt/GSK-3β信号通路对NMDA受体的直接调节作用。与抗精神病药物氯氮平一样，LY 379268急性治疗显著增加了NMDA受体以及Akt和GSK-3β的表达和磷酸化。在生理上，LY 379268显著增强前额叶神经元中NMDA诱导的电流，GSK-3β抑制剂阻断了这种作用。与广泛提出的调节突触前谷氨酸释放的机制相反，我们的研究结果有力地表明，mGluR 2/3激动剂通过突触后作用调节NMDA受体的功能，并通过Akt/GSK-3β通路逆转MK-801诱导的NMDA功能障碍。本研究为mGluR 2/3调节NMDA受体的突触后机制提供了新的证据，并对mGluR 2/3激动剂作为治疗精神分裂症的潜在抗精神病药物的机制作用提供了有用的见解。
Pharmacological intervention targeting mGluRs has emerged as a potential treatment for schizophrenia, whereas the mechanisms involved remain elusive. We explored the antipsychotic effects of a 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.
登录
查看更多内容
影响因子：
--
作者：
Conn, P. Jeffrey;Tamminga, Carol;Lindsley, Craig
通讯作者：
Lindsley, Craig
DOI：
10.1196/annals.1300.008
发表时间：
2003-01-01
期刊：
GLUTAMATE AND DISORDERS OF COGNITION AND MOTIVATION
影响因子：
--
作者：
Farber, NB
通讯作者：
Farber, NB
影响因子：
3.4
作者：
Cartmell, J;Monn, JA;Schoepp, DD
通讯作者：
Schoepp, DD
影响因子：
16.2
作者：
Barria, A;Malinow, R
通讯作者：
Malinow, R
影响因子：
30.8
作者：
Emamian, ES;Hall, D;Gogos, JA
通讯作者：
Gogos, JA