Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany.
Carl Ludwig Institute for Physiology, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany.
Cell Rep. 2019 Jul 2;28(1):11-20.e9. doi: 10.1016/j.celrep.2019.06.005.
Myosin VI is an actin-based cytoskeletal motor implicated in various steps of membrane trafficking. Here, we investigated whether this myosin is crucial for synaptic function and plasticity in neurons. We find that myosin VI localizes at cerebellar parallel fiber to Purkinje cell synapses and that the myosin is indispensable for long-term depression of AMPA-receptor-mediated synaptic signal transmission at this synapse. Moreover, direct visualization of GluA2-containing AMPA receptors in Purkinje cells reveals that the myosin drives removal of AMPA receptors from the surface of dendritic spines in an activity-dependent manner. Co-immunoprecipitation and super-resolution microscopy indicate that specifically the interaction of myosin VI with the clathrin adaptor component α-adaptin is important during long-term depression. Together, these data suggest that myosin VI directly promotes clathrin-mediated endocytosis of AMPA receptors in Purkinje cells to mediate cerebellar long-term depression. Our results provide insights into myosin VI function and the molecular mechanisms underlying synaptic plasticity.
肌球蛋白 VI 是一种参与膜运输各个步骤的肌动球蛋白细胞骨架马达。在这里，我们研究了这种肌球蛋白是否对神经元中的突触功能和可塑性至关重要。我们发现肌球蛋白 VI 定位于小脑平行纤维到浦肯野细胞突触，并且该肌球蛋白对于该突触上 AMPA 受体介导的突触信号传递的长时程抑制是必不可少的。此外，直接可视化浦肯野细胞中的 GluA2 包含的 AMPA 受体表明，肌球蛋白以活动依赖性方式从树突棘表面驱动 AMPA 受体的去除。免疫共沉淀和超分辨率显微镜表明，在长时程抑制期间，肌球蛋白 VI 与网格蛋白衔接蛋白成分 α-衔接蛋白的特异性相互作用很重要。总之，这些数据表明肌球蛋白 VI 直接促进浦肯野细胞中 AMPA 受体的网格蛋白介导内吞作用，以介导小脑长时程抑制。我们的结果为肌球蛋白 VI 功能和突触可塑性的分子机制提供了新的见解。
