A role for myosin Va in cerebellar plasticity and motor learning: A possible mechanism underlying neurological disorder in myosin Va disease

Abstract

Mutations of the myosin Va gene cause the neurological diseases Griscelli syndrome type 1 and Elejalde syndrome in humans and dilute phenotypesinrodents.To understand the pathophysiological mechanisms underlying the neurological disordersinmyosin Vadiseases, we conducted an integrated analysis at the molecular, cellular, electrophysiological, and behavioral levels using the dilute-neurological (d-n) mousemutant. These micemanifestanataxicgaitandclonicseizuresduringpostnataldevelopment, buttheneurological disorders are amelioratedin adulthood. We found that smooth endoplasmic reticulum (SER) rarely extended into the dendritic spines of Purkinje cells (PCs) of young d-n mice, and there were few, if any, IP3 receptors. Moreover, long-term depression (LTD) at parallel fiber-PC synapses was abolished, consistent with our previous observations in juvenile lethal dilute mutants. Young d-n mice exhibited severe impairment of cerebellum-dependent motor learning. In contrast, adult d-n mice showed restoration of motor learning and LTD, and these neurological changes were associated with accumulationofSER and IP3 receptorsin some PC spines and the expression of myosin Va proteins in the PCs. RNA interference-mediated repression of myosin Va caused a reduction in the number of IP3 receptor-positive spinesincultured PCs. These findings indicate that myosin Va functioniscritical for subsequent processesinlocalization ofSER and IP3 receptors in PC spines, LTD, and motor learning. Interestingly, d-n mice had defects of motor coordination from young to adult ages, suggesting that the role of myosin Va in PC spines is not sufficient for motor coordination. © 2011 the authors.