https://scholars.lib.ntu.edu.tw/handle/123456789/506159
標題: | Cerebellar oscillations driven by synaptic pruning deficits of cerebellar climbing fibers contribute to tremor pathophysiology | 作者: | MING-KAI PAN Li Y.-S. Wong S.-B. Ni C.-L. Wang Y.-M. Liu W.-C. Lu L.-Y. Lee J.-C. Cortes E.P. Vonsattel J.-P.G. Sun Q. Louis E.D. Faust P.L. Kuo S.-H. |
公開日期: | 2020 | 卷: | 12 | 期: | 526 | 起(迄)頁: | eaay1769 | 來源出版物: | Science Translational Medicine | 摘要: | 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. Copyright ? 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/506159 | ISSN: | 1946-6234 | DOI: | 10.1126/scitranslmed.aay1769 | SDG/關鍵字: | glutamate receptor 2; glutamate receptor; glutamate receptor delta 2; adult; animal experiment; animal model; Article; brain tissue; cell synchronization; cerebellum; climbing fiber; clinical article; cohort analysis; controlled study; disease severity; essential tremor; firing rate; human; human cell; human tissue; in vivo study; mouse; nervous system electrophysiology; nonhuman; optogenetics; oscillation; oscillatory potential; pathophysiology; priority journal; protein analysis; protein expression; Purkinje cell; synapse; animal; cerebellum; metabolism; pathology; synapse; tremor; Animals; Cerebellum; Humans; Mice; Purkinje Cells; Receptors, Glutamate; Synapses; Tremor |
顯示於: | 藥理學科所 |
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