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首页> 外文期刊>Nature Communications >Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice
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Altered surface mGluR5 dynamics provoke synaptic NMDAR dysfunction and cognitive defects in Fmr1 knockout mice

机译:改变的表面mGluR5动力学引起Fmr1基因敲除小鼠的突触NMDAR功能障碍和认知缺陷

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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.
机译:代谢型谷氨酸受体亚型5(mGluR5)与脆性X综合征(FXS)的病理生理密切相关。然而,其在亚细胞水平上的功能障碍以及相关的突触和认知表型尚待探索。在这里,我们探讨了第二代Fmr1基因敲除(KO)小鼠中mGluR5 / Homer支架破坏对mGluR5细胞表面迁移性,突触N-甲基-D-天冬氨酸受体(NMDAR)功能和行为表型的影响。使用单分子跟踪,我们发现在海马Fmr1 KO神经元的突触中,mGluR5明显更具移动性,从而导致mGluR5和NMDAR的突触表面共簇增加。这与突触NMDAR电流幅度降低,缺乏其mGluR5激活的长期抑郁症以及NMDAR /海马依赖性认知缺陷有关。通过击倒Fmr1 KO小鼠中的Homer1a,可以逆转这些突触和行为现象。我们的研究提供了mGluR5动力学变化与FXS病理表型之间的机制联系,揭示了基于mGluR5的治疗药物的新靶标。

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