Journal
JOURNAL OF NEUROSCIENCE
Volume 26, Issue 48, Pages 12576-12586Publisher
SOC NEUROSCIENCE
DOI: 10.1523/JNEUROSCI.3080-06.2006
Keywords
calcium channel; mouse mutant; alpha(2)delta subunit; mutation; spontaneous firing; Purkinje cell
Categories
Funding
- MRC [G0100503] Funding Source: UKRI
- Medical Research Council [G0100503] Funding Source: researchfish
- Medical Research Council [G0100503] Funding Source: Medline
- Wellcome Trust [061497] Funding Source: Medline
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The mouse mutant ducky and its allele ducky(2J) represent a model for absence epilepsy characterized by spike-wave seizures and cerebellar ataxia. These mice have mutations in Cacna2d2, which encodes the alpha(2)delta-2 calcium channel subunit. Of relevance to the ataxic phenotype, alpha(2)delta-2 mRNA is strongly expressed in cerebellar Purkinje cells (PCs). The Cacna2d2(du2J) mutation results in a 2 bp deletion in the coding region and a complete loss of alpha(2)delta-2 protein. Here we show that du(2J)/du(2J) mice 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 degrees C, du(2J)/du(2J) PCs show no spontaneous intrinsic activity. Du(2J)/du(2J) mice also have alterations in the cerebellar expression of several genes related to PC function. At postnatal day 21, there is an elevation of tyrosine hydr degrees oxylase mRNA and a reduction in tenascin-C gene expression. Although du(2J)/+ mice have a marked reduction in alpha(2)delta 2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tryrosine hydroxylase gene expression. However, du(2J)/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in alpha(2)delta-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 alpha(2)delta-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.
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