The general goal of this research is to understand the etiology of human neurologic disorders by using animal models to identify the abnormal genetic, molecular and cellular pathways that finally result in the clinical manifestation of the mutation. Mutant strains of mice are proving to be useful animal models in determining the mechanisms underlying inherited disorders of the nervous system. The tottering (tg) mouse mutant has been extensively studied as a mouse model of epilepsy. These mice exhibit a triad of neuropathologies including spike and wave discharges, myoclonus and ataxia. The tg mutation is also associated with two distinct cellular abnormalities: hyperarborization of noradrenergic fibers arising from the locus ceruleus and aberrant expression of tyrosine hydroxylase (TH) in cerebellar Purkinje cells. However, the role of these cellular anomalies in the expression of the abnormal phenotype is not yet clear nor has the tg gene yet been identified. The goal of this proposal is to trace the mutation from gene to behavior to begin to piece together the series of molecular and cellular events that ultimately give rise to the expression of the tottering phenotype.
The specific aims of this proposal are: l) to isolate the tg gene. The tottering mouse phenotype provides few clues to the specific mutation. However, our preliminary data suggest specific brain regions, developmental timepoints and an exact chromosome location for the tg gene, making identification of this gene possible for the first time. 2) to identify the neuroanatomical substrates of myoclonus in tottering mice. We have recently discovered how to induce myoclonus in tottering mice. By using markers of neuronal activation during a tottering mouse myoclonic episode, these experiments will determine if there is an obligatory temporal and anatomical progression of neuronal recruitment that occurs in the expression of myoclonus. 3) to determine the precise relationship of noradrenergic innervation to the expression and development of the tottering phenotype. Although the noradrenergic hyperinnervation arising from the tottering mouse LC contributes to the spike and wave discharges, the effect of this hyperarborization on the expression and development of myoclonus, ataxia and Purkinje cell TH expression has not been studied. The results of this proposal will furnish new insights into the disease process resulting in the tottering mouse phenotype which may be generalized to the genesis and maintenance of epilepsies and/or ataxia in humans.
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