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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.

SUBMITTER: Miyata M

PROVIDER: S-EPMC6632970 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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

Miyata Mariko M Kishimoto Yasushi Y Tanaka Masahiko M Hashimoto Kouichi K Hirashima Naohide N Murata Yoshiharu Y Kano Masanobu M Takagishi Yoshiko Y

The Journal of neuroscience : the official journal of the Society for Neuroscience 20110401 16

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 devel ...[more]

PMID: 21508232

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Project description:The robust, reciprocal anatomical connections between the cerebellum and contralateral sensorimotor cerebral hemisphere underscores the strong physiological interdependence between these two regions in relation to human behavior. Previous studies have shown that damage to sensorimotor cortex can result in a lasting reduction of cerebellar metabolism, the magnitude of which has been linked to poor rehabilitative outcomes. A better understanding of movement-related cerebellar physiology as well as cortico-cerebellar coherence (CCC) in the chronic, post-stroke state may be key to developing novel neuromodulatory techniques that promote upper limb motor rehabilitation. As a part of the first in-human phase-I trial investigating the effects of deep brain stimulation of the cerebellar dentate nucleus (DN) on chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG in subjects (both sexes) with middle cerebral artery stroke during a visuo-motor tracking task. We investigated the excitability of ipsilesional cortex, DN and the their interaction as a function of motor impairment and performance. Our results indicate that 1) event-related oscillations in the ipsilesional cortex and DN were significantly correlated at movement onset in the low-β band, with moderately and severely impaired subjects showing desynchronization and synchronization, respectively. 2) Significant CCC was observed during isometric 'hold' period in the low-β band, which was critical for maintaining task accuracy. Our findings support a strong coupling between ipsilesional cortex and DN in the low-β band during motor control across all impairment levels which encourages the exploitation of the cerebello-thalamo-cortical pathway as a neuromodulation target to promote rehabilitation.Significance Statement:Cerebral infarct due to stroke can lead to lasting reduction in cerebellar metabolism resulting in poor rehabilitative outcomes. Thorough investigation of the cerebellar electrophysiology as well as cortico-cerebellar connectivity in humans that could provide key insights to facilitate development of novel neuromodulatory technologies, has been lacking. As a part of the first in-human phase-I trial investigating deep brain stimulation of the cerebellar dentate nucleus (DN) for chronic, post-stroke motor rehabilitation, we collected invasive recordings from DN and scalp EEG while stroke patients performed a motor task. Our data indicate strong coupling between ipsilesional sensorimotor cortex and DN in the low-β band across all impairment levels encouraging the exploration of electrical stimulation of the DN.

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

Publications

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

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