Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.
Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice.
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DOI：
10.1038/s41467-017-01191-2
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发表时间：
2017-10-24
影响因子：
16.6
通讯作者：
Frick A
中科院分区：
文献类型：
--
作者：
Aloisi E;Le Corf K;Dupuis J;Zhang P;Ginger M;Labrousse V;Spatuzza M;Georg Haberl M;Costa L;Shigemoto R;Tappe-Theodor A;Drago F;Vincenzo Piazza P;Mulle C;Groc L;Ciranna L;Catania MV;Frick A
代谢型谷氨酸受体亚型5（mGluR 5）在脆性X综合征（FXS）的病理生理学中至关重要;然而，其在亚细胞水平的功能障碍以及相关的突触和认知表型尚未探索。在这里，我们探讨了mGluR 5/荷马支架破坏mGluR 5细胞表面的流动性，突触N-甲基-D-天冬氨酸受体（NMDAR）的功能，在第二代Fmr 1敲除（KO）小鼠的行为表型的后果。使用单分子追踪，我们发现mGluR 5在海马Fmr 1 KO神经元的突触处显著更移动的，导致mGluR 5和NMDAR的突触表面共聚集增加。这与突触NMDAR电流的幅度降低、缺乏其mGluR 5激活的长期抑制和NMDAR/海马依赖性认知缺陷相关。这些突触和行为现象通过敲低Fmr 1 KO小鼠中的Homer 1a而逆转。我们的研究提供了mGluR 5动力学变化与FXS病理表型之间的机制联系，揭示了基于mGluR 5的治疗方法的新靶点。mGluR 5的功能障碍与脆性X综合征有关。在这里，使用单分子追踪技术，作者发现在Fmr 1 KO海马神经元的突触部位，mGluR 5的侧向移动性增加，导致异常的NMDAR介导的突触可塑性和认知缺陷。
Metabotropic glutamate receptor subtype 5 (mGluR5) is crucially implicated in the pathophysiology of Fragile X Syndrome (FXS); however, its dysfunction at the sub-cellular level, and related synaptic and cognitive phenotypes are unexplored. Here, we probed the consequences of mGluR5/Homer scaffold disruption for mGluR5 cell-surface mobility, synaptic N-methyl-D-aspartate receptor (NMDAR) function, and behavioral phenotypes in the second-generation Fmr1 knockout (KO) mouse. Using single-molecule tracking, we found that mGluR5 was significantly more mobile at synapses in hippocampal Fmr1 KO neurons, causing an increased synaptic surface co-clustering of mGluR5 and NMDAR. This correlated with a reduced amplitude of synaptic NMDAR currents, a lack of their mGluR5-activated long-term depression, and NMDAR/hippocampus dependent cognitive deficits. These synaptic and behavioral phenomena were reversed by knocking down Homer1a in Fmr1 KO mice. Our study provides a mechanistic link between changes of mGluR5 dynamics and pathological phenotypes of FXS, unveiling novel targets for mGluR5-based therapeutics. Dysfunction of mGluR5 has been implicated in Fragile X syndrome. Here, using a single-molecule tracking technique, the authors found an increased lateral mobility of mGluR5 at the synaptic site in Fmr1 KO hippocampal neurons, leading to abnormal NMDAR-mediated synaptic plasticity and cognitive deficits.
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影响因子：
3
作者：
Costa L;Sardone LM;Lacivita E;Leopoldo M;Ciranna L
通讯作者：
Ciranna L
影响因子：
5.7
作者：
Anggono V;Huganir RL
通讯作者：
Huganir RL
影响因子：
5.3
作者：
Groc, Laurent;Lafourcade, Mathieu;Cognet, Laurent
通讯作者：
Cognet, Laurent
影响因子：
8.2
作者：
D'Antoni S;Spatuzza M;Bonaccorso CM;Musumeci SA;Ciranna L;Nicoletti F;Huber KM;Catania MV
通讯作者：
Catania MV
影响因子：
25
作者：
Goncalves, J. Tiago;Anstey, James E.;Golshani, Peyman;Portera-Cailliau, Carlos
通讯作者：
Portera-Cailliau, Carlos