Vestibulocerebellar function in channelopathy mutants

小脑是在头部运动过程中稳定眼睛的神经回路的关键组成部分，小脑的紊乱会降低视力。其确切的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保持了很高的程度。研究改变这些保守特征的影响将有助于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在P型钙通道中携带突变的小鼠品系，该突变集中在小脑中，并且在定义浦肯野细胞的电生理学特征方面起着关键作用。该项目将描述具有P通道突变的小鼠的眼运动异常，并使用神经元记录来证明这些异常与小脑信号处理紊乱有关。具体目标1和2将检验以下假设：代偿性眼球运动（如前庭眼反射，VOR）的动态和空间特征在突变株中紊乱。特定目标3将检验突变体在改变VOR增益或方向的能力方面具有特定缺陷的假设。具体目标1-3将共同确定一组适用于电生理技术后续研究的异常。具体目标4将通过测试下橄榄（也表达P-通道）功能障碍作为突变体眼部异常的来源可以被消除的假设来启动电生理学研究。钙通道突变与人类疾病如家族性偏头痛和发作性共济失调有关。因此，这项研究产生的对正常小脑功能的见解也应该促进我们对遗传性神经疾病机制的理解。

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.