The Role of BK Channels in Oculomotor Plasticity

描述（由申请人提供）：本研究的长期目标是了解调节眼球运动正常表现和适应性可塑性的细胞和分子机制。前庭-眼反射和光动力反射（分别为VOR和光动力反射）通过产生眼部运动来精确补偿头部运动，从而防止自我运动过程中的视力模糊。神经元的可塑性机制使这些反射在面对发育、创伤和疾病时能够准确地执行。尽管特定类型的神经元在信号转换和可塑性方面的作用已经被确定，但对于细胞机制如何促进动眼肌系统的日常表现和适应能力，人们知之甚少。本研究的目的是阐明一种特殊类型的离子通道，即bk型钙活化钾通道，在诱导和维持动眼肌可塑性中的作用。核心假设是BK电流的调节在由外周功能障碍和长时间视觉-前庭失配经历引起的VOR和OKR的适应性变化中起关键作用。拟议的研究将在转基因小鼠中使用行为和电生理分析相结合的方法来研究需要BK通道的动眼肌可塑性的形式以及BK通道在动眼肌回路中的关键位置。来自小脑小叶的细胞外记录将补充浦肯野细胞中BK通道整体或特异性缺失小鼠的行为分析。这些研究将为有针对性地研究小脑依赖性可塑性的分子机制以及引起眼球震颤的动眼病的药物治疗提供基础。

DESCRIPTION (provided by applicant): The long-range goal of this research is to understand the cellular and molecular mechanisms that mediate the normal performance and adaptive plasticity in eye movements. The vestibulo-ocular and optokinetic reflexes (VOR and OKR, respectively) prevent blurred vision during self-motion by producing eye movements that precisely compensate for motion of the head. Neuronal mechanisms of plasticity enable these reflexes to perform accurately in the face of development, trauma, and disease. Although the roles of particular classes of neurons to signal transformations and plasticity have been identified, little is understood about how cellular mechanisms contribute to the day-to-day performance and adaptive capabilities of the oculomotor system. The objective of this proposal is to elucidate the role of a particular type of ion channel, the BK-type calcium activated potassium channel, in the induction and maintenance of oculomotor plasticity. The central hypothesis is that regulation of BK currents plays a critical role in adaptive changes in the VOR and OKR induced both by peripheral dysfunction and by prolonged visual-vestibular mismatch experience. The proposed research will use a combination of behavioral and electrophysiological analyses in transgenic mice to investigate the forms of oculomotor plasticity that require BK channels and the critical locations of BK channels within the oculomotor circuit. Extracellular recordings from the cerebellar flocculus will complement behavioral analyses of mice in which BK channels are deleted either globally or specifically in Purkinje cells. These studies will provide foundations for targeted investigations of the molecular mechanisms that underlie cerebellar-dependent plasticity as well as for pharmacological treatments of oculomotor disorders that cause nystagmus.