Principles of Therapy in Cerebellar Disease: Explorations in Ion Channel Mutants

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DESCRIPTION (provided by applicant): Today's neurologists have few therapies to offer patients suffering the limb ataxia, imbalance, and visual impairment resulting from diseases of the cerebellum. Such patients are common in the veteran population and becoming more so due to traumatic brain injuries suffered in recent military operations. Recent developments, however, suggest that highly effective drugs can be developed: Two drugs that influence neuronal potassium channels have been shown to ameliorate cerebellar deficits in humans and mice, and may provide starting points to develop more efficacious and tolerable drugs. However, the sources of their therapeutic effects are debatable. Likewise, a new theory that ataxia can originate in disturbed rhythmicity of cerebellar Purkinje cells suggests procedures for drug development, but the theory is controversial and requires more investigation. This project will lay a better groundwork for drug development by clarifying the origins of cerebellar motor dysfunction and mechanism of one existing treatment. We focus on ocular motility abnormalities in mice carrying mutations of the CACNA1A gene of the P/Q (CaV2.1) calcium channel, but the results should be applicable to other causes and manifestations of cerebellar dysfunction. Specific Aim 1 involves eye movement recordings in the CACNA1A mutant tottering, and in normal mice following pharmacological inhibition of the cerebellar flocculus, to determine the cause of the abnormal vertical eye positions found in ataxic mice. The result will determine whether mice can be used to test treatments for downbeat nystagmus, a human manifestation of cerebellar disease that results in blurred vision. Specific Aim 2 tests the theory that ataxia in calcium channel mutants originates in disturbed Purkinje cell rhythmicity, through recordings of Purkinje cells in the flocculus and anterior vermis of normal mice and the CACNA1A mutant rocker. One goal of these recordings is to determine whether rocker Purkinje cells exhibit, as the rhythmicity theory predicts, rhythmicity intermediate between that of normal animals and the more severely affected CACNA1A mutant, tottering. Another goal of the recordings is to reassess whether CACNA1A mutant Purkinje cells modulate their firing normally in response to natural stimulation. This claim is central to the rhythmicity theory, but the experiments that support the claim may have been affected by sampling bias. Specific aim 3 assesses the therapeutic mechanisms of 4- aminopyridine, one of the drugs that has recently been shown to provide some benefits in cerebellar disorders. We will record eye movements in tottering following systemic and intrafloccular injections of 4- aminopyridine. Results of these experiments will allow us to test published speculations that aminopyridines exert their beneficial effects by restoring normal Purkinje cell activity.