Characterization of a Murine Model of Spinocerebellar Ataxia 13 (S18.006)

Objective: To characterize and analyze a novel transgenic murine model for Spinocerebellar ataxia 13. Background: Our study focuses on the rare autosomal dominant Spinocerebellar Ataxia 13 (SCA13), caused by mutations in the voltage-gated potassium channel KCNC3 (Kv3.3). We previously confirmed causation of SCA13 by the KCNC3 p.Arg423His allele through neurological and genetic characterization of four families. The clinical features demonstrate congenital onset with non-progressive, neurodevelopmental cerebellar hypoplasia with the patients displaying a lifetime improvement in motor and cognitive function, suggestive of compensatory neural mechanisms. To further our understanding of this disease, we have now created a murine model for SCA13 and present results from its behavioral and histopathological characterization. Design/Methods: A BAC construct containing the human p.Arg423His KCNC3 locus was introduced into mouse embryos and one of the subsequent founder lines was used for all analyses. Gait and tremor characterization of the mice was done with an in-house rig and software. Histopathology was analyzed by sectioning and immunostaining the mouse brains at different ages. Other behavioral analysis (Rotarod, open field) was performed per manufacturer’s instructions. Results: The BAC p.Arg423His KCNC3 model displays severe and progressive behavioral abnormalities in gait and coordination, with a strong tremor. The histopathological results show extensive and progressive loss of Purkinje cells with increased astrocyte activation and microgliosis. Conclusions: We have thus established and characterized a transgenic murine SCA13 model for future therapeutic and basic research. Disclosure: Dr. Khare has nothing to disclose. Dr. Nick has nothing to disclose. Dr. Niemczyk has nothing to disclose. Dr. Sanborn has nothing to disclose. Dr. Lewis has nothing to disclose. Dr. Nick has nothing to disclose. Dr. Waters has nothing to disclose.