A role for myosin VI in postsynaptic structure and glutamate receptor endocytosis

• DOI: 10.1083/jcb.200410091
• Publication Date: 2005-01-18T22:58:16Z
• Authors: Emily Osterweil; David G. Wells; Mark S. Mooseker
• Keywords: Male; 0301 basic medicine; Sucrose; Dendritic Spines; Synaptic Membranes; Adaptor Protein Complex 2; Nerve Tissue Proteins; Myosins; Discs Large Homolog 1 Protein; Mice; 03 medical and health sciences; Adenosine Triphosphate; Glial Fibrillary Acidic Protein; Animals; Insulin; Receptors, AMPA; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; Research Articles; Adaptor Proteins, Signal Transducing; Neurons; Brain Chemistry; Myosin Heavy Chains; Microfilament Proteins; Transferrin; Brain; Dyneins; Membrane Proteins; Dendrites; Guanylate Kinase; Mice, Mutant Strains; Endocytosis; 3. Good health; Mice, Inbred C57BL; Microscopy, Electron; Receptors, Glutamate; Astrocytes; Synapses; Female; Guanylate Kinases; Synaptosomes

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 α-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.