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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
1R01EY013370-01A1
Application #
6438428
Study Section
Visual Sciences B Study Section (VISB)
Program Officer
Hunter, Chyren
Project Start
2002-02-05
Project End
2005-01-31
Budget Start
2002-02-05
Budget End
2003-01-31
Support Year
1
Fiscal Year
2002
Total Cost
$229,500
Indirect Cost
Name
Case Western Reserve University
Department
Neurology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Stahl, John S; Thumser, Zachary C (2012) Dynamics of abducens nucleus neurons in the awake mouse. J Neurophysiol 108:2509-23
Stahl, John S; Oommen, Brian S (2008) Eye hyperdeviation in mouse cerebellar mutants is comparable to the gravity-dependent component of human downbeat nystagmus. Prog Brain Res 171:503-8
Oommen, Brian S; Stahl, John S (2008) Eye orientation during static tilts and its relationship to spontaneous head pitch in the laboratory mouse. Brain Res 1193:57-66
Stahl, John S; James, Robert A; Oommen, Brian S et al. (2006) Eye movements of the murine P/Q calcium channel mutant tottering, and the impact of aging. J Neurophysiol 95:1588-607
Stahl, John S; James, Robert A (2005) Neural integrator function in murine CACNA1A mutants. Ann N Y Acad Sci 1039:580-2
Yin, Hang; Stahl, John S; Andrade, Francisco H et al. (2005) Eliminating the Ant1 isoform produces a mouse with CPEO pathology but normal ocular motility. Invest Ophthalmol Vis Sci 46:4555-62
Alagramam, Kumar N; Stahl, John S; Jones, Sherri M et al. (2005) Characterization of vestibular dysfunction in the mouse model for Usher syndrome 1F. J Assoc Res Otolaryngol 6:106-18
Stahl, John S (2004) Eye movements of the murine P/Q calcium channel mutant rocker, and the impact of aging. J Neurophysiol 91:2066-78
Stahl, John S (2004) Using eye movements to assess brain function in mice. Vision Res 44:3401-10
McMullen, Colleen A; Andrade, Francisco H; Stahl, John S (2004) Functional and genomic changes in the mouse ocular motor system in response to light deprivation from birth. J Neurosci 24:161-9