Cerebellar ataxia, a devastating neurological disease, may be initiated by hyperexcitability of deep cerebellar nuclei (DCN) secondary to loss of inhibitory input from Purkinje neurons that frequently degenerate in this disease. This mechanism predicts that intrinsic DCN hyperexcitability would cause ataxia in the absence of upstream Purkinje degeneration. A transgenic (Tg) model that we developed supports this mechanism of disease initiation. In this transgenic model, small-conductance calcium-activated potassium (SK) channels, regulators of firing frequency in deep cerebellar neurons, were silenced in the CNS 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. Neurodegeneration was not evident up to the sixth month of age. In the attached video, the transgenic mouse exhibits ataxia exhibited as an inability to balance on a slowly rotating rotorod. The mouse falls off the rotorod in a few seconds in contrast to normal mice that can balance on the rotorod. Thus, a purely electrical alteration in the deep cerebellar ataxia is sufficient to cause cerebellar ataxia. Approaches that slow down firing in the deep cerebellar neurons may ameliorate the symptoms of 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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