Cerebellar ataxia is a devastating neurological disease. We have developed a transgenic mouse model that suggests that cerebellar ataxia may be initiated by hyperexcitability of deep cerebellar nuclei (DCN). Small-conductance calcium-activated potassium (SK) channels, regulators of firing frequency, were silenced in deep cerebellar neurons of Tg mice with the dominant-inhibitory construct SK3-1B-GFP. Transgene expression was restricted to the DCN within the cerebellum and was detectable beginning on postnatal day 10, concomitant with the onset of cerebellar ataxia. In the attached video, a normal littermate balances normally on the slowly rotating rotorod and does not fall off. Please compare this video with that of the SK3-1B-GFP transgenic mouse that is unable to balance on the rotorod and falls off. Our results suggest that a purely electrical change in the deep cerebellar neurons may lead to the symptoms of cerebellar ataxia, and a therapy that slows down firing in these neurons may ameliorate cerebellar ataxia.
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Shakkottai VG, Chou CH, Oddo S, Sailer CA, Knaus HG, Gutman GA, Barish ME, LaFerla FM, Chandy KG. Enhanced neuronal excitability in the absence of neurodegeneration induces cerebellar ataxia. J Clin Invest. 2004 Feb;113(4):582-90
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