Vestibulocerebellar function in channelopathy mutants

通道病突变体的前庭小脑功能

• 批准号: 6622048
• 负责人: JOHN SAMUEL STAHL
• 金额: $ 26.78万
• 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/6622048
• 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.

小脑是在头部运动时稳定眼睛的神经回路的关键组成部分，小脑的紊乱会一致地降低视力。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结构和电导在进化过程中得到高度保守。研究改变这一保守特征的效果将使我们深入了解它们所支持的计算过程。这种方法现在是可行的，因为遗传学和分子生物学的研究已经确定了P型钙通道存在突变的小鼠品系，P型钙通道集中在小脑，在确定浦肯野细胞的电生理特征方面发挥着关键作用。该项目将表征P通道突变小鼠的眼运动异常，并使用神经元记录来证明这些异常与小脑信号处理障碍有关。具体目标1和2将检验这样的假设，即在突变菌株中，代偿性眼球运动(如前庭眼球反射，VOR)的动态和空间特征是紊乱的。具体目标3将检验这样一种假设，即突变体在改变VOR的增益或方向的能力方面存在特定缺陷。总之，特定的AIMS 1-3将识别一组适合于随后使用电生理技术进行研究的异常。具体目标4将通过测试下橄榄(也表达P通道)的功能障碍可以作为突变体眼睛异常的来源而被消除的假设来启动电生理学研究。钙通道突变与家族性偏头痛和发作性共济失调等人类疾病有关。因此，这项研究对正常小脑功能的洞察也应该促进我们对遗传性神经疾病机制的理解。