| Abstract No.: | C-C3083 |
| Country: | Canada |
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| Title: | MISSENSE MUTATION IN THE KV1.2 POTASSIUM CHANNEL CAUSES CEREBELLAR DYSFUNCTION AND ATAXIA IN PINGU MICE |
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| Authors/Affiliations: | 4 Gang Xie; 2 John M. Harrison*; 4 Steven J. Clapcote; 1 Yun Huang; 3 Lu-Yang Wang; 5 John C. Roder;
1 Dept. of Medicine Univ. of Toronto; 2 Hosp. for Sick Children; 3 Hosp. for Sick Children; Univ. of Toronto; 4 Samuel Lunenfeld Research Inst.; 5 Samuel Lunenfeld Research Inst. ; University of Toronto, ON, Canada
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| Content: | Potassium channel mutations and dysfunction have been implicated in numerous neurological disorders. Here we report the first case of an N-ethyl-N-nitrosourea (ENU) induced missense mutation, Pingu (Pgu), replacing an isoleucine with a threonine at position 402 of the voltage-gated potassium channel Kcna2. Pgu mutant mice exhibited prominent and chronic motor incoordination and were smaller than wild-type littermates; both effects of the mutation being more pronounced in homozygotes compared to heterozygotes. Transgenic complementation, with wild-type Kcna2 cDNA, reduced the severity of, but did not eliminate the persistent motor incoordination in Pgu mice. The motor deficits and ataxia associated with the Pgu mutant mice suggested that synaptic transmission in the cerebellum, which is involved in the coordination of complex motor tasks, may be altered in Pgu mutants. Basket cells, spontaneously firing cerebellar GABAergic molecular layer interneurons, provide a powerful tonic level of inhibition to the soma of Purkinje cells, which generate the sole output of the cerebellum. The presynaptic “basket structure” of this axo-somatic synapse has the highest levels of Kv1.2 subunit expression in the entire brain. The functioning of the presynaptic basket cell terminal, and as a result GABAergic inhibition, was therefore a likely candidate to be affected by the Pgu Kcna2 mutation. Electrophysiological recordings revealed that the Pgu mutation increased both the frequency and the amplitude of spontaneous GABAergic inhibitory postsynaptic currents (IPSCs) without affecting miniature IPSCs, and consequentially reduced the firing frequency of cerebellar Purkinje cells. In contrast, the firing frequency of basket cells remained unaltered, suggesting that the observed motor incoordination is due to an increase in GABA release from the basket cell terminals onto Purkinje cells. The mouse Kcna2 Pgu mutation presents a new genetic locus for motor disorders and suggests the potential involvement of human Kv1.2 channel dysfunction in human ataxic neurological disorders.
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