The ducky2JMutation inCacna2d2Results in Reduced Spontaneous Purkinje Cell Activity and Altered Gene Expression

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Abstract
The mouse mutant ducky and its allele ducky2Jrepresent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations inCacna2d2, which encodes the α2δ-2 calcium channel subunit. Of relevance to the ataxic phenotype, α2δ-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). TheCacna2d2du2Jmutation results in a 2 bp deletion in the coding region and a complete loss of α2δ-2 protein. Here we show thatdu2J/du2Jmice have a 30% reduction in somatic calcium current and a marked fall in the spontaneous PC firing rate at 22°C, accompanied by a decrease in firing regularity, which is not affected by blocking synaptic input to PCs. At 34°C,du2J/du2JPCs show no spontaneous intrinsic activity.Du2J/du2Jmice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydroxylase mRNA and a reduction in tenascin-C gene expression. Althoughdu2J/+ mice have a marked reduction in α2δ-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tryrosine hydroxylase gene expression. However,du2J/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in α2δ-2. A hypothesis for future study is that effects on gene expression occur as a result of a reduction in somatic calcium currents, whereas effects on PC firing occur as a long-term result of loss of α2δ-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.