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Published 18 January 2005. doi:10.1083/jcb.200410091
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 168, Number 2, 329-338
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Article

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



Emily Osterweil1, David G. Wells1, and Mark S. Mooseker1,2,3

1 Department of Molecular, Cellular and Developmental Biology
2 Department of Cell Biology, Yale University, New Haven, CT 06511
3 Department of Pathology, Yale University, New Haven, CT 06511

Correspondence to Emily Osterweil: emily.osterweil{at}yale.edu

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.

Abbreviations used in this paper: AMPA, {alpha}-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid; AMPAR, AMPA-type glutamate receptor; dnM6, dominant-negative Myo6; DOC, deoxycholate; GaR, goat anti–rabbit; GFAP, glial fibrillary acidic protein; IP, immunoprecipitation; LTD, long-term depression; Myo6, myosin VI; Myo7a, myosin VIIa; NMDAR, N-methyl-D-aspartate–type glutamate receptor; PSD, postsynaptic density; Tf, transferrin; TTX, tetrodotoxin; TX, Triton X-100.


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