A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis.
Myosin VI (Myo6) is an actin-based motor protein implicated in clathrin-mediated endocytosis in nonneuronal cells, though little is known about its function in the nervous system. Here, we find that Myo6 is highly expressed throughout the brain, localized to synapses, and enriched at the postsynaptic density. Myo6-deficient (Snell's waltzer; sv/sv) hippocampus exhibits a decrease in synapse number, abnormally short dendritic spines, and profound astrogliosis. Similarly, cultured sv/sv hippocampal neurons display decreased numbers of synapses and dendritic spines, and dominant-negative disruption of Myo6 in wild-type hippocampal neurons induces synapse loss. Importantly, we find that sv/sv hippocampal neurons display a significant deficit in the stimulation-induced internalization of alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid-type glutamate receptors (AMPARs), and that Myo6 exists in a complex with the AMPAR, AP-2, and SAP97 in brain. These results suggest that Myo6 plays a role in the clathrin-mediated endocytosis of AMPARs, and that its loss leads to alterations in synaptic structure and astrogliosis.
Osterweil
Emily
E
Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT 06511, USA. emily.osterweil@yale.edu
Wells
David G
DG
Mooseker
Mark S
MS
D033962:Adaptor Protein Complex 2 / Q000378:metabolism; D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate / Q000494:pharmacology; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000648:ultrastructure; D001921:Brain / Q000378:metabolism / Q000648:ultrastructure; D001923:Brain Chemistry; D003712:Dendrites / Q000378:metabolism / Q000648:ultrastructure; D049229:Dendritic Spines / Q000378:metabolism / Q000648:ultrastructure; D000074288:Discs Large Homolog 1 Protein; D004398:Dyneins / Q000235:genetics / Q000378:metabolism; D004705:Endocytosis / Q000187:drug effects / Q000502:physiology*; D005260:Female; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D051528:Guanylate Kinases; D007328:Insulin / Q000494:pharmacology; D008297:Male; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D008840:Microfilament Proteins / Q000032:analysis / Q000378:metabolism; D008854:Microscopy, Electron; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000081412:Myosin VIIa; D009218:Myosins / Q000235:genetics / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000032:analysis / Q000378:metabolism; D009474:Neurons / Q000502:physiology / Q000648:ultrastructure; D018091:Receptors, AMPA / Q000032:analysis / Q000378:metabolism*; D017470:Receptors, Glutamate / Q000378:metabolism; D013395:Sucrose / Q000494:pharmacology; D013569:Synapses / Q000502:physiology* / Q000648:ultrastructure; D013570:Synaptic Membranes / Q000737:chemistry / Q000187:drug effects; D013574:Synaptosomes / Q000737:chemistry / Q000187:drug effects; D014168:Transferrin / Q000378:metabolism; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid / Q000378:metabolism; D000099273:Neurabins
D033962:Adaptor Protein Complex 2; D048868:Adaptor Proteins, Signal Transducing; D000255:Adenosine Triphosphate; D000074288:Discs Large Homolog 1 Protein; D004398:Dyneins; D005904:Glial Fibrillary Acidic Protein; D051528:Guanylate Kinases; D007328:Insulin; D008565:Membrane Proteins; D008840:Microfilament Proteins; D018995:Myosin Heavy Chains; D000081412:Myosin VIIa; D009218:Myosins; D009419:Nerve Tissue Proteins; D018091:Receptors, AMPA; D017470:Receptors, Glutamate; D013395:Sucrose; D014168:Transferrin; D018350:alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; D000099273:Neurabins; C000614189:Dlg1 protein, mouse; C000631456:Myo7a protein, mouse; C089785:myosin VI; C033652:postsynaptic density proteins; C104722:glutamate receptor ionotropic, AMPA 2