Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214.
Department of Physiology and Biophysics, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York 14214.
J Biol Chem. 2012 Mar 23;287(13):10265-10275. doi: 10.1074/jbc.M111.325175. Epub 2012 Jan 27.
Emerging evidence suggests that metabotropic glutamate receptors (mGluRs) are potential novel targets for brain disorders associated with the dysfunction of prefrontal cortex (PFC), a region critical for cognitive and emotional processes. Because N-methyl-D-aspartic acid receptor (NMDAR) dysregulation has been strongly associated with the pathophysiology of mental illnesses, we examined the possibility that mGluRs might be involved in modulating PFC functions by targeting postsynaptic NMDARs. We found that application of prototypical group III mGluR agonists significantly reduced NMDAR-mediated synaptic and ionic currents in PFC pyramidal neurons, which was mediated by mGluR7 localized at postsynaptic neurons and involved the β-arrestin/ERK signaling pathway. The mGluR7 modulation of NMDAR currents was prevented by agents perturbing actin dynamics and by the inhibitor of cofilin, a major actin-depolymerizing factor. Consistently, biochemical and immunocytochemical results demonstrated that mGluR7 activation increased cofilin activity and F-actin depolymerization via an ERK-dependent mechanism. Furthermore, mGluR7 reduced the association of NMDARs with the scaffolding protein PSD-95 and the surface level of NMDARs in an actin-dependent manner. These data suggest that mGluR7, by affecting the cofilin/actin signaling, regulates NMDAR trafficking and function. Because ablation of mGluR7 leads to a variety of behavioral symptoms related to PFC dysfunction, such as impaired working memory and reduced anxiety and depression, our results provide a potential mechanism for understanding the role of mGluR7 in mental health and disorders.
新出现的证据表明，代谢型谷氨酸受体（mGluRs）可能是与前额叶皮层（PFC）功能障碍相关的脑疾病的潜在新靶点，PFC 是认知和情绪过程的关键区域。由于 N-甲基-D-天冬氨酸受体（NMDAR）失调与精神疾病的病理生理学密切相关，我们研究了 mGluRs 通过靶向突触后 NMDAR 调节 PFC 功能的可能性。我们发现，典型的 III 组 mGluR 激动剂的应用显著降低了 PFC 锥体神经元中 NMDAR 介导的突触和离子电流，这是由突触后神经元中定位的 mGluR7 介导的，涉及β-arrestin/ERK 信号通路。mGluR7 对 NMDAR 电流的调制可通过扰乱肌动蛋白动力学的试剂和肌动蛋白解聚因子 cofilin 的抑制剂来预防。一致地，生化和免疫细胞化学结果表明，mGluR7 通过 ERK 依赖性机制激活增加了肌动蛋白解聚因子 cofilin 的活性和 F-肌动蛋白解聚。此外，mGluR7 以肌动蛋白依赖的方式减少了 NMDAR 与支架蛋白 PSD-95 的结合以及 NMDAR 的表面水平。这些数据表明，mGluR7 通过影响 cofilin/actin 信号通路来调节 NMDAR 的转运和功能。由于 mGluR7 的缺失导致与 PFC 功能障碍相关的各种行为症状，如工作记忆受损、焦虑和抑郁减少，因此我们的结果为理解 mGluR7 在心理健康和障碍中的作用提供了一种潜在的机制。
