PMID:16474392

Citation	Walter, JT, Alviña, K, Womack, MD, Chevez, C and Khodakhah, K (2006) Decreases in the precision of Purkinje cell pacemaking cause cerebellar dysfunction and ataxia. Nat. Neurosci. 9:389-97
Abstract	Episodic ataxia type-2 (EA2) is caused by mutations in P/Q-type voltage-gated calcium channels that are expressed at high densities in cerebellar Purkinje cells. Because P/Q channels support neurotransmitter release at many synapses, it is believed that ataxia is caused by impaired synaptic transmission. Here we show that in ataxic P/Q channel mutant mice, the precision of Purkinje cell pacemaking is lost such that there is a significant degradation of the synaptic information encoded in their activity. The irregular pacemaking is caused by reduced activation of calcium-activated potassium (K(Ca)) channels and was reversed by pharmacologically increasing their activity with 1-ethyl-2-benzimidazolinone (EBIO). Moreover, chronic in vivo perfusion of EBIO into the cerebellum of ataxic mice significantly improved motor performance. Our data support the hypothesis that the precision of intrinsic pacemaking in Purkinje cells is essential for motor coordination and suggest that K(Ca) channels may constitute a potential therapeutic target in EA2.
Links	PubMed Online version:10.1038/nn1648
Keywords	Action Potentials/drug effects; Action Potentials/genetics; Animals; Benzimidazoles/pharmacology; Biological Clocks/drug effects; Biological Clocks/genetics; Calcium Channel Agonists/pharmacology; Calcium Channel Blockers/pharmacology; Calcium Channels, P-Type/drug effects; Calcium Channels, P-Type/genetics; Cerebellar Ataxia/genetics; Cerebellar Ataxia/metabolism; Cerebellar Ataxia/physiopathology; Cerebellar Cortex/drug effects; Cerebellar Cortex/metabolism; Cerebellar Cortex/physiopathology; Down-Regulation/genetics; Female; Male; Mice; Mice, Neurologic Mutants; Mice, Transgenic; Potassium Channels, Calcium-Activated/genetics; Purkinje Cells/drug effects; Purkinje Cells/metabolism; Purkinje Cells/pathology; Synaptic Membranes/genetics; Synaptic Membranes/metabolism; Synaptic Membranes/pathology; Synaptic Transmission/drug effects; Synaptic Transmission/genetics
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