Myosin VI Drives Clathrin-Mediated AMPA Receptor Endocytosis to Facilitate Cerebellar Long-Term Depression

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. [Display omitted] •MYO6 is present at cerebellar parallel fiber-Purkinje cell synapses•Parallel fiber-Purkinje cell LTD is impaired in Snell’s waltzer and by MYO6 inhibitor•MYO6 mediates removal of surface AMPA receptors from Purkinje cell spines during LTD•MYO6 interaction with clathrin adaptor component α-adaptin increases during LTD Wagner et al. investigate the cellular mechanisms that underlie synaptic plasticity in neurons and find that the actin-based cytoskeletal motor myosin VI is directly required for activity-induced, clathrin-mediated endocytosis of AMPA receptors in cerebellar Purkinje cells and for synaptic long-term depression at parallel fiber-Purkinje cell synapses.