Episodic channelopathies are characterized by a mild baseline phenotype interrupted by attacks of severe symptoms induced by the same set of triggers, namely alcohol, caffeine, and emotional or physical stress. Episodic ataxia type two(EA2) is one such disorder that arises from mutations in the gene encoding for the P/Q-type voltage-gated calcium channel. The tottering, a mouse model of EA2, carries a mutation in the same gene as human EA2 patients. As a result, the tottering exhibits an ataxic baseline phenotype with severe attacks of abnormal movements, known as dyskinesia, triggered by ethanol, caffeine and stress. The intermittent nature of these attacks and their appearance in response to the same triggers as in human patients make tottering a tractable model of an episodic neurological disorder. The mechanism by which mutations in the P/Q-type calcium channel lead to dyskinesia and how triggers induce such episodes is unknown. The cerebellum has been implicated in the pathogenesis of dyskinesia, however its contribution is yet to be determined. Purkinje cells are the principal neurons of the cerebellar cortex and the regularity of their pacemaking has been implicated in many forms of ataxia. We propose to investigate the physiological basis of the sensorimotor attacks in EA2 and the site of action of different triggers in tottering. Our goal is to determine if changes in the intrinsic activity of Purkinje cells can mediate dyskinesia, and if triggers' effect on the cerebellum can induce such episodes. To address this question, we performed extracellular recordings from single Purkinje cells in the awake tottering mouse in the presence and absence of dyskinesia attacks, and found that the regularity of Purkinje cell activity is significantly altered during such attacks triggered by physiological doses of caffeine, ethanol or stress.
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