The ducky(2J) mutation in Cacna2d2 results in reduced spontaneous Purkinje cell activity and altered gene expression

• Published in: The Journal of neuroscience Vol. 26; no. 48; pp. 12576 - 12586
• Main Authors: Donato, Roberta, Page, Karen M, Koch, Dietlind, Nieto-Rostro, Manuela, Foucault, Isabelle, Davies, Anthony, Wilkinson, Tonia, Rees, Michele, Edwards, Frances A, Dolphin, Annette C
• Format: Journal Article
• Language: English
• Published: United States 29.11.2006
• Subjects: Animals; Calcium Channels - genetics; Calcium Channels - physiology; Chlorocebus aethiops; COS Cells; Gene Expression Regulation - genetics; In Vitro Techniques; Mice; Mice, Knockout; Mice, Transgenic; Mutation; Purkinje Cells - metabolism; Purkinje Cells - pathology
• ISSN: 1529-2401
• DOI: 10.1523/JNEUROSCI.3080-06.2006

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.