Essential tremor (ET) is one of the most common movement disorders and the prototypical disorder for abnormal rhythmic movements. However, the pathophysiology of tremor generation in ET remains unclear. Here, we used autoptic cerebral tissue from patients with ET, clinical data, and mouse models to report that synaptic pruning deficits of climbing fiber (CF)-to-Purkinje cell (PC) synapses, which are related to glutamate receptor delta 2 (GluRδ2) protein insufficiency, cause excessive cerebellar oscillations and might be responsible for tremor. The CF-PC synaptic pruning deficits were correlated with the reduction in GluRδ2 expression in the postmortem ET cerebellum. Mice with GluRδ2 insufficiency and CF-PC synaptic pruning deficits develop ET-like tremor that can be suppressed with viral rescue of GluRδ2 protein. Step-by-step optogenetic or pharmacological inhibition of neuronal firing, axonal activity, or synaptic vesicle release confirmed that the activity of the excessive CF-to-PC synapses is required for tremor generation. In vivo electrophysiology in mice showed that excessive cerebellar oscillatory activity is CF dependent and necessary for tremor and optogenetic-driven PC synchronization was sufficient to generate tremor in wild-type animals. Human validation by cerebellar electroencephalography confirmed that excessive cerebellar oscillations also exist in patients with ET. Our findings identify a pathophysiologic contribution to tremor at molecular (GluRδ2), structural (CF-to-PC synapses), physiological (cerebellar oscillations), and behavioral levels (kinetic tremor) that might have clinical applications for treating ET.

中文翻译：

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由小脑攀爬纤维的突触修剪缺陷驱动的小脑振荡有助于震颤的病理生理学。

特发性震颤（ET）是最常见的运动障碍之一，也是异常节律性运动的典型障碍。然而，ET 中震颤产生的病理生理学仍不清楚。在这里，我们使用来自 ET 患者的尸检脑组织、临床数据和小鼠模型来报告攀爬纤维 (CF) 到浦肯野细胞 (PC) 突触的突触修剪缺陷，这与谷氨酸受体 delta 2 (GluRδ2 ) 蛋白质不足，导致小脑过度振荡，并可能导致震颤。CF-PC 突触修剪缺陷与死后 ET 小脑中 GluRδ2 表达的减少相关。GluRδ2 不足和 CF-PC 突触修剪缺陷的小鼠会出现 ET 样震颤，这种震颤可以通过病毒拯救 GluRδ2 蛋白来抑制。对神经元放电、轴突活动或突触小泡释放的逐步光遗传学或药理学抑制证实了过度的 CF 到 PC 突触的活动是震颤产生所必需的。小鼠体内电生理学表明，过度的小脑振荡活动是 CF 依赖性的，并且是震颤所必需的，并且光遗传学驱动的 PC 同步足以在野生型动物中产生震颤。通过小脑脑电图进行的人体验证证实，ET 患者也存在过度的小脑振荡。我们的研究结果确定了分子（GluRδ2）、结构（CF-to-PC 突触）、生理（小脑振荡）和行为水平（运动性震颤）对震颤的病理生理贡献，可能对治疗 ET 有临床应用。