John S. Stahl - US grants

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.