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Publication Detail
The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Comparative Study
  • Authors:
    Donato R, Page KM, Koch D, Nieto-Rostro M, Foucault I, Davies A, Wilkinson T, Rees M, Edwards FA, Dolphin AC
  • Publication date:
    29/11/2006
  • Pagination:
    12576, 12586
  • Journal:
    J Neurosci
  • Volume:
    26
  • Issue:
    48
  • Status:
    Published
  • Country:
    United States
  • PII:
    26/48/12576
  • Language:
    eng
  • Keywords:
    Animals, COS Cells, Calcium Channels, Chlorocebus aethiops, Gene Expression Regulation, In Vitro Techniques, Mice, Mice, Knockout, Mice, Transgenic, Mutation, Purkinje Cells
Abstract
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 alpha2delta-2 calcium channel subunit. Of relevance to the ataxic phenotype, alpha2delta-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 alpha2delta-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 degrees 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 hydroxylase mRNA and a reduction in tenascin-C gene expression. Although du(2J)/+ mice have a marked reduction in alpha2delta-2 protein, they show no fall in PC somatic calcium currents or increase in cerebellar tyrosine hydroxylase gene expression. However, du(2J)/+ PCs do exhibit a significant reduction in firing rate, correlating with the reduction in alpha2delta-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 alpha2delta-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.
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