MyosinVa (MyoVa) mediates F-actin-based vesicular transport toward the plasma membrane and is found at neuronal postsynaptic densities (PSDs), but the role of MyoVa in synaptic development and function is largely unknown. Here, in studies using the dominant negative MyoVa neurological mutant mouse Flailer, we find that MyoVa plays an essential role in activity-dependent delivery of PSD-95 and other critical PSD molecules to synapses and in endocytosis of AMPA-type glutamate receptors (AMPAR) in the dendrites of CNS neurons. MyoVa is known to carry a complex containing the major scaffolding proteins of the mature PSD, PSD-95, SAPAP1/GKAP, Shank and Homer, to dendritic spine synapses. In Flailer, neurons show abnormal dendritic shaft localization of PSD-95, stargazin, dynamin3, AMPA glutamate receptors (AMPARs) and abnormal spine morphology. Flailer neurons also have abnormally high AMPAR miniature current frequencies and spontaneous AMPAR currents that are more frequent and larger than in WT while numbers of NMDAR containing synapses remain normal. The AMPAR abnormalities are consistent with a severely disrupted developmental regulation of long-term depression that we find in cortical Flailer neurons. Thus MyoVa plays a fundamentally important role both in localizing mature glutamate synapses to spines and in organizing the synapse for normal function. For this reason Flailer mice will be valuable in further dissecting the role of MyoVa in normal synaptic and circuit refinement and also in studies of neurological and neuropsychiatric diseases where disruptions of normal glutamate synapses are frequently observed.
and Technology (SFRH/BD/33726/2009) as a graduate student and by the McGovern Institute for Brain Research as a postdoctoral fellow. FJB was a Simons center for the Social Brain Postdoctoral Fellow at MIT and a Pew Latin American Postdoctoral Fellow. FJB is funded by FONDECYT 11180540 and CONICYT-PAI 77180077. We thank Prof. Glen Prusky and Nazia Alam, Weill Cornell Medical College for helping us with the visual acuity test; Stanley Center, Prof. Mriganka Sur's Lab and Prof. Gouping Feng's Lab for behavioral equipment; Prof. Tomaso Poggio and Nicholas Edelman for development and setting up of the automated phenotyping system for mouse grooming behavior.
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