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The Journal of Neuroscience, November 29, 2006, 26(48):12576-12586; doi:10.1523/JNEUROSCI.3080-06.2006

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Neurobiology of Disease
The ducky^2J Mutation in Cacna2d2 Results in Reduced Spontaneous Purkinje Cell Activity and Altered Gene Expression

Roberta Donato,^2 * Karen M. Page,^1 * Dietlind Koch,¹ Manuela Nieto-Rostro,¹ Isabelle Foucault,¹ Anthony Davies,¹ Tonia Wilkinson,³ Michele Rees,³ Frances A. Edwards,² and Annette C. Dolphin¹

Departments of ¹Pharmacology and ²Physiology, University College London, and ³Department of Paediatrics and Child Health, Royal Free and University College Medical School, London WC1E 6BT, United Kingdom

Correspondence should be addressed to Dr. Annette C. Dolphin, Laboratory of Cellular and Molecular Neuroscience, Andrew Huxley Building, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.dolphin{at}ucl.ac.uk

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 ₂-2 calcium channel subunit. Of relevance to the ataxic phenotype, ₂-2 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 ₂-2 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°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 ₂-2 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 ₂-2. 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 ₂-2 and/or a reduction in calcium currents and calcium-dependent processes in regions other than the soma.

Key words: calcium channel; mouse mutant; ₂ subunit; mutation; spontaneous firing; Purkinje cell

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Received July 20, 2006; revised Oct. 23, 2006; accepted Oct. 25, 2006.

Correspondence should be addressed to Dr. Annette C. Dolphin, Laboratory of Cellular and Molecular Neuroscience, Andrew Huxley Building, Department of Pharmacology, University College London, Gower Street, London WC1E 6BT, UK. Email: a.dolphin{at}ucl.ac.uk

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