title: 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 phenotypes in rodents. To understand the pathophysiological mechanisms underlying the neurological disorders in myosin Va diseases, we conducted an integrated analysis at the molecular, cellular, electrophysiological, and behavioral levels using the dilute-neurological (d-n) mouse mutant. These mice manifest an ataxic gait and clonic seizures during postnatal development, but the neurological disorders are ameliorated in 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, IP(3) 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 accumulation of SER and IP(3) receptors in 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 IP(3) receptor-positive spines in cultured PCs. These findings indicate that myosin Va function is critical for subsequent processes in localization of SER and IP(3) 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.
authors.affiliation: Department of Physiology, Tokyo Women's Medical University School of Medicine, Tokyo 162-8666, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Miyata
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Kishimoto
authors.forename: Masahiko
authors.initials: M
authors.lastname: Tanaka
authors.forename: Kouichi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Naohide
authors.initials: N
authors.lastname: Hirashima
authors.forename: Yoshiharu
authors.initials: Y
authors.lastname: Murata
authors.forename: Masanobu
authors.initials: M
authors.lastname: Kano
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Takagishi
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D002531:Cerebellum / Q000502:physiology*; D003214:Conditioning, Classical / Q000502:physiology; D003215:Conditioning, Eyelid / Q000502:physiology; D049229:Dendritic Spines / Q000378:metabolism; D004594:Electrophysiology; D018871:Endoplasmic Reticulum, Smooth / Q000378:metabolism; D007150:Immunohistochemistry; D053496:Inositol 1,4,5-Trisphosphate Receptors / Q000378:metabolism; D007858:Learning / Q000502:physiology*; D051379:Mice; D008818:Mice, Neurologic Mutants; D009043:Motor Activity / Q000502:physiology*; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism*; D024701:Myosin Type V / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000502:physiology*; D009474:Neurons / Q000502:physiology*; D045442:Rotarod Performance Test; D013569:Synapses / Q000502:physiology
chemical_list: D053496:Inositol 1,4,5-Trisphosphate Receptors; C513082:Myo5a protein, mouse; D024701:Myosin Type V; D018995:Myosin Heavy Chains