A Role for Myosin Va in Cerebellar Plasticity and Motor Learning: A Possible Mechanism Underlying Neurological Disorder in Myosin Va Disease
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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DOI：
10.1523/jneurosci.5651-10.2011
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发表时间：
2011-04-20
影响因子：
5.3
通讯作者：
Takagishi, Yoshiko
中科院分区：
文献类型：
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作者：
Miyata, Mariko;Kishimoto, Yasushi;Takagishi, Yoshiko
肌球蛋白Va基因突变导致人类神经系统疾病Griscelli综合征1型和Elejalde综合征，并稀释啮齿动物的表型。为了了解肌球蛋白Va疾病中神经系统疾病的病理生理机制，我们使用稀释神经（d-n）小鼠突变体在分子、细胞、电生理和行为水平上进行了综合分析。这些小鼠在出生后发育期间表现出共济失调步态和阵挛性癫痫发作，但神经系统疾病在成年后得到改善。我们发现，滑面内质网（SER）很少延伸到年轻的d-n小鼠浦肯野细胞（PC）的树突棘，有几个，如果有的话，IP 3受体。此外，长期抑郁症（LTD）在平行的纤维PC突触被废除，与我们以前的观察一致，在青少年致死稀释突变体。年幼的d-n小鼠表现出严重的小脑依赖性运动学习障碍。相反，成年d-n小鼠表现出运动学习和LTD的恢复，这些神经系统的变化与积累的SER和IP 3受体在一些PC的棘和表达的肌球蛋白Va蛋白的PC。RNA干扰介导的肌球蛋白Va的抑制导致培养的PC中IP 3受体阳性棘的数量减少。这些研究结果表明，肌球蛋白Va功能是至关重要的后续过程中的本地化的SER和IP 3受体在PC的脊柱，LTD，和运动学习。有趣的是，d-n小鼠从幼年到成年都有运动协调缺陷，这表明前交叉韧带棘中肌球蛋白Va的作用不足以促进运动协调。
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, 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 accumulation of SER and IP3 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 IP3 receptor-positive spines in cultured PCs. These findings indicate that myosin Va function is critical for subsequent processes in localization of SER 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.