Vestibulocerebellar function in channelopathy mutants

通道病突变体的前庭小脑功能

• 批准号: 6438428
• 负责人: JOHN SAMUEL STAHL
• 金额: $ 22.95万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-02-05 至 2005-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6438428
• 关键词: biological signal transduction; calcium channel; cerebellar cortex; cerebellar disorders; electrophysiology; eye movement disorders; gene mutation; head movements; laboratory mouse; neurons; vestibuloocular reflex; video recording system

The cerebellum is a critical component of the neural circuitry that stabilizes the eyes during head movements, and disorders of the cerebellum uniformly degrade vision. Its exact computational role remains controversial, but a key to its function may lie in the high degree to which the unique architecture and conductances of its neurons have been conserved though evolution. Studying the effects of altering this conserved features would give insight into the computational processes they support. This approach is now feasible, as research in genetics and molecular biology has identified mouse strains harboring mutations in the P-type calcium channel, which is concentrated in the cerebellum and plays a key role in defining the electrophysiological characteristics of the Purkinje cell. This project will characterize the ocular motor abnormalities of mice with P-channel mutations, and use neuronal recordings to prove that these abnormalities are referable to disordered cerebellar signal processing. Specific Aim 1 and 2 will test the hypothesis that the dynamic and spatial characteristics of compensatory eye movements (such as vestibulo-ocular reflex, VOR), are disordered in the mutant strains. Specific aim 3 will test the hypothesis that mutants have specific deficits in the ability to alter the gain or direction of the VOR. Together, specific aims 1-3 will identify a set of abnormalities suitable for subsequent investigation with electrophysiological techniques. Specific aim 4 will initiate the electrophysiological investigation by testing the hypothesis that dysfunction in the inferior olive (which also expressed the P-channel) can be eliminated as a source of the mutants' ocular abnormalities. Calcium channel mutations have been implicated in human diseases such as familial migraine and episodic ataxia. Thus, the insights into normal cerebellar function generated by this study should also advance our understanding of mechanisms of heritable neurological disease.

小脑是神经回路的关键组成部分，在头部运动过程中稳定眼睛，小脑的疾病均匀地降低了视力。它的确切计算作用仍然存在争议，但其功能的关键可能在于其神经元的独特架构和电导的高度，尽管进化了。研究改变这种保守特征的效果将洞悉其支持的计算过程。现在，这种方法是可行的，因为在遗传学和分子生物学方面的研究已经确定了在P型钙通道中携带突变的小鼠菌株，该通道集中在小脑中，并在定义Purkinje细胞的电生理特征方面起着关键作用。该项目将表征具有P通道突变的小鼠的眼运动异常，并使用神经元记录证明这些异常是指小脑信号处理。具体的目标1和2将检验以下假设：在突变菌株中，补偿性眼运动的动态和空间特征（例如前庭 - 眼反射，VOR）是无序的。特定目标3将检验以下假设：突变体在改变VOR的增益或方向的能力方面具有特定的缺陷。总之，具体目标1-3将确定一组适合随后使用电生理技术研究的异常。特定目标4将通过测试以下假设来启动电生理研究，即可以消除下橄榄（也表达了P通道）的功能障碍作为突变体的眼异常的来源。钙通道突变与家族性偏头痛和情节性共济失调等人类疾病有关。因此，这项研究产生的对正常小脑功能的见解也应提高我们对可遗传神经疾病机制的理解。