Department of Molecular and Cellular Physiology and.
Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, California, USA.
J Clin Invest. 2020 Oct 1;130(10):5142-5156. doi: 10.1172/JCI135802.
Essential tremor is a common brain disorder affecting millions of people, yet the neuronal mechanisms underlying this prevalent disease remain elusive. Here, we showed that conditional deletion of synaptotagmin-2, the fastest Ca2+ sensor for synaptic neurotransmitter release, from parvalbumin neurons in mice caused an action tremor syndrome resembling the core symptom of essential tremor patients. Combining brain region-specific and cell type-specific genetic manipulation methods, we found that deletion of synaptotagmin-2 from excitatory parvalbumin-positive neurons in cerebellar nuclei was sufficient to generate an action tremor. The synaptotagmin-2 deletion converted synchronous into asynchronous neurotransmitter release in projections from cerebellar nuclei neurons onto gigantocellular reticular nucleus neurons, which might produce an action tremor by causing signal oscillations during movement. The tremor was rescued by completely blocking synaptic transmission with tetanus toxin in cerebellar nuclei, which also reversed the tremor phenotype in the traditional harmaline-induced essential tremor model. Using a promising animal model for action tremor, our results thus characterized a synaptic circuit mechanism that may underlie the prevalent essential tremor disorder.
特发性震颤是一种常见的脑部疾病，影响着数百万人，但其潜在的神经元机制仍难以捉摸。在这里，我们发现条件性敲除小鼠小脑浦肯野细胞中突触结合蛋白-2（一种用于突触神经递质释放的最快的 Ca2+传感器）会导致类似于特发性震颤患者核心症状的动作震颤综合征。通过结合脑区特异性和细胞类型特异性的遗传操作方法，我们发现从小脑核神经元中敲除突触结合蛋白-2足以产生动作震颤。突触结合蛋白-2 的缺失将小脑核神经元投射到巨细胞网状核神经元上的同步神经递质释放转换为异步释放，这可能通过在运动过程中产生信号振荡而导致动作震颤。用破伤风毒素完全阻断小脑核中的突触传递可以挽救震颤，这也逆转了传统哈尔明诱导的特发性震颤模型中的震颤表型。利用一种有前途的动作震颤动物模型，我们的研究结果因此描述了一种可能是特发性震颤这种常见疾病潜在的突触回路机制。
