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The Journal of Neuroscience, August 15, 2001, 21(16):6095-6104

Ducky Mouse Phenotype of Epilepsy and Ataxia Is Associated with Mutations in the Cacna2d2 Gene and Decreased Calcium Channel Current in Cerebellar Purkinje Cells

Jane Barclay¹, Nuria Balaguero², Marina Mione³, Susan L. Ackerman⁴, Verity A. Letts⁴, Jens Brodbeck², Carles Canti², Alon Meir², Karen M. Page², Kenro Kusumi⁵, Edward Perez-Reyes⁶, Eric S. Lander⁵, Wayne N. Frankel⁴, R. Mark Gardiner¹, Annette C. Dolphin², and Michele Rees¹

¹ Department of Paediatrics and Child Health, Royal Free and University College Medical School, The Rayne Institute, London, WC1E 6JJ, United Kingdom, Departments of ² Pharmacology and ³ Anatomy and Developmental Biology, University College London, London, WC1E 6BT, United Kingdom, ⁴ The Jackson Laboratory, Bar Harbor, Maine 04609, ⁵ Whitehead Institute for Biomedical Research, Cambridge, Massachusetts 02142, and ⁶ Department of Pharmacology, University of Virginia Health System, Charlottesville, Virginia 22908-0735

The mouse mutant ducky, a model for absence epilepsy, is characterized by spike-wave seizures and ataxia. The ducky gene was mapped previously to distal mouse chromosome 9. High-resolution genetic and physical mapping has resulted in the identification of the Cacna2d2 gene encoding the 22 voltage-dependent calcium channel subunit. Mutations in Cacna2d2 were found to underlie the ducky phenotype in the original ducky (du) strain and in a newly identified strain (du^2J). Both mutations are predicted to result in loss of the full-length 22 protein. Functional analysis shows that the 22 subunit increases the maximum conductance of the 1A/4 channel combination when coexpressed in vitro in Xenopus oocytes. The Ca²⁺ channel current in acutely dissociated du/du cerebellar Purkinje cells was reduced, with no change in single-channel conductance. In contrast, no effect on Ca²⁺ channel current was seen in cerebellar granule cells, results consistent with the high level of expression of the Cacna2d2 gene in Purkinje, but not granule, neurons. Our observations document the first mammalian 2 mutation and complete the association of each of the major classes of voltage-dependent Ca²⁺ channel subunits with a phenotype of ataxia and epilepsy in the mouse.

Key words: epilepsy; ataxia; calcium channel; subunit; Purkinje cell; cerebellum; mouse mutant

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Copyright © 2001 Society for Neuroscience  0270-6474/01/21166095-10$05.00/0

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