The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease
The mGluR5 positive allosteric modulator VU0409551 improves synaptic plasticity and memory of a mouse model of Huntington's disease
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DOI：
10.1111/jnc.14555
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发表时间：
2018-10-01
影响因子：
4.7
通讯作者：
Ribeiro, Fabiola M.
中科院分区：
文献类型：
--
作者：
Doria, Juliana G.;de Souza, Jessica M.;Ribeiro, Fabiola M.
亨廷顿舞蹈病（HD）是一种常染色体显性神经退行性疾病，以不自主的身体运动、认知障碍和精神障碍为特征。代谢性谷氨酸受体5 （mGluR5）在HD中起着重要作用，我们最近证明mGluR5阳性的变构调节剂（pam）可以改善HD小鼠模型的病理和表型信号。在本研究中，我们研究了mGluR5 PAMs对记忆影响的分子机制。我们的研究结果表明，用mGluR5 PAM VU0409551进行亚慢性治疗可以有效地逆转HD小鼠模型BACHD小鼠表现出的记忆缺陷。此外，VU0409551处理稳定了BACHD小鼠细胞膜上的mGluR5，增加了对突触可塑性重要的几个基因的表达，包括c-Fos、脑源性神经营养因子、Arc/Arg3.1、syntaxin 1A和突触后密度-95。此外，VU0409551处理也增加了树突棘密度和成熟度，增加了突触前位点的数量。综上所述，我们的研究结果表明，VU0409551触发了突触可塑性重要的细胞信号通路的激活，提高了树突棘成熟水平，并挽救了BACHD记忆障碍。
Huntington's Disease (HD) is an autosomal-dominant neurodegenerative disorder, characterized by involuntary body movements, cognitive impairment, and psychiatric disorder. The metabotropic glutamate receptor 5 (mGluR5) plays an important role in HD and we have recently demonstrated that mGluR5-positive allosteric modulators (PAMs) can ameliorate pathology and the phenotypic signs of a mouse model of HD. In this study, we investigated the molecular mechanisms involved in mGluR5 PAMs effect on memory. Our results demonstrate that subchronic treatment with the mGluR5 PAM VU0409551 was effective in reversing the memory deficits exhibited by BACHD mice, a mouse model for HD. Moreover, VU0409551 treatment stabilized mGluR5 at the cellular plasma membrane of BACHD mice, increasing the expression of several genes important for synaptic plasticity, including c-Fos, brain-derived neurotrophic factor, Arc/Arg3.1, syntaxin 1A, and post-synaptic density-95. In addition, VU0409551 treatment also increased dendritic spine density and maturation and augmented the number of pre-synaptic sites. In conclusion, our results demonstrate that VU0409551 triggered the activation of cell signaling pathways important for synaptic plasticity, enhancing the level of dendritic spine maturation and rescuing BACHD memory impairment.