Cerebellar Function in Health and Disease

[unreadable] DESCRIPTION (provided by applicant): Several forms of hereditary ataxia such as episodic ataxia type 2 (EA2) and spinocerebellar ataxia type 6 (SCA6) are caused by mutations in P/Q-type voltage-gated calcium channels. The main objective of this grant is to test a new hypothesis regarding the cause of ataxia in patients suffering from these movement disorders. Malfunction of the cerebellum, either because of pathological damage or alterations in the physiological function of its neurons, results in uncoordinated movement (ataxia). In humans and mice several forms of hereditary ataxia have been identified. Many of these are the consequence of mutations in the P/Q-type voltage-gated calcium channels which are present throughout the central nervous system (CNS). P/Q-type calcium channels are expressed throughout the CNS and trigger neurotransmitter release at many nerve terminals. The accepted hypothesis suggests that in P/Q-channel related ataxias poor motor coordination is the consequence of impaired synaptic transmission in the cerebellum. Reported changes in synaptic transmission, however, do not fully account for the extent of ataxia. This grant examines whether additional cerebellar defects contribute to ataxia in these disorders. In the cerebellum P/Q channels are expressed at a high density in the soma and dendrites of Purkinje cells. Purkinje cells form the core of the computational units of the cerebellum and their dysfunction causes ataxia. In Purkinje cells of the ataxic P/Q-channel mutants the P/Q calcium current is significantly reduced. Further, in different mutant mice, the severity of ataxia correlates well with the extent of reduction in the P/Q current in Purkinje cells. We have previously shown that in Purkinje cells P/Q-type calcium channels regulate firing by activating calcium-activated potassium channels. Here we propose that P/Q channel mutations that cause ataxia alter the intrinsic, spontaneous, firing of Purkinje cells. Because Purkinje cells provide the sole output of the cerebellar cortex large alterations in their intrinsic firing will impair their function. Such dysfunction is likely to make a significant contribution to poor motor coordination. We will examine whether the intrinsic firing of Purkinje cells is altered in the P/Q-channel mutant mice, and if so, we will explore whether agents that make the firing of P/Q mutant Purkinje cells regular reduce ataxia. [unreadable] [unreadable] [unreadable]