1. The ducky2JMutation inCacna2d2Results in Reduced Spontaneous Purkinje Cell Activity and Altered Gene Expression
- Author
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Anthony Davies, Dietlind Koch, Annette C. Dolphin, Karen M. Page, Frances A. Edwards, Tonia Wilkinson, Roberta Donato, M Rees, Manuela Nieto-Rostro, and Isabelle Foucault
- Subjects
Purkinje cell ,chemistry.chemical_element ,Mice, Transgenic ,In Vitro Techniques ,Calcium ,Biology ,Article ,Mice ,Purkinje Cells ,03 medical and health sciences ,0302 clinical medicine ,Chlorocebus aethiops ,Gene expression ,medicine ,Animals ,030304 developmental biology ,Mice, Knockout ,Regulation of gene expression ,0303 health sciences ,Tyrosine hydroxylase ,Voltage-dependent calcium channel ,Cerebellar ataxia ,General Neuroscience ,Calcium channel ,Cell biology ,medicine.anatomical_structure ,Gene Expression Regulation ,chemistry ,COS Cells ,Mutation ,Calcium Channels ,medicine.symptom ,Neuroscience ,030217 neurology & neurosurgery - 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.
- Published
- 2006