Myosin VI Drives Clathrin-Mediated AMPA Receptor Endocytosis to Facilitate Cerebellar Long-Term Depression
Wolfgang Wagner,
Kristina Lippmann,
Frank F. Heisler,
Kira V. Gromova,
Franco L. Lombino,
Mona K. Roesler,
Yvonne Pechmann,
Sönke Hornig,
Michaela Schweizer,
Simona Polo,
Jürgen R. Schwarz,
Jens Eilers,
Matthias Kneussel
Affiliations
Wolfgang Wagner
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Corresponding author
Kristina Lippmann
Carl Ludwig Institute for Physiology, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
Frank F. Heisler
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Kira V. Gromova
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Franco L. Lombino
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Mona K. Roesler
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Yvonne Pechmann
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Sönke Hornig
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Michaela Schweizer
Electron Microscopy Unit, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Simona Polo
Fondazione Istituto FIRC di Oncologia Molecolare (IFOM), 20139 Milan, Italy; Dipartimento di Oncologia ed Emato-oncologia, Università degli Studi di Milano, 20122 Milan, Italy
Jürgen R. Schwarz
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany
Jens Eilers
Carl Ludwig Institute for Physiology, Medical Faculty, University of Leipzig, 04103 Leipzig, Germany
Matthias Kneussel
Department of Molecular Neurogenetics, Center for Molecular Neurobiology (ZMNH), University Medical Center Hamburg-Eppendorf, 20251 Hamburg, Germany; Corresponding author
Summary: 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. : 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. Keywords: actin cytoskeleton, AMPA receptor, cerebellum, clathrin-mediated endocytosis, dendritic spines, long-term depression, motor protein, myosin, Myo6, Purkinje cell, synaptic plasticity