Cerebellum (2012) 11:246–258 DOI 10.1007/s12311-011-0302-1 ORIGINAL PAPER Purkinje Cell-Specific Ablation of CaV2.1 Channels is Sufficient to Cause Cerebellar Ataxia in Mice Boyan Todorov & Lieke Kros & Reinald Shyti & Petra Plak & Elize D. Haasdijk & Robert S. Raike & Rune R. Frants & Ellen J. Hess & Freek E. Hoebeek & Chris I. De Zeeuw & Arn M. J. M. van den Maagdenberg Published online: 26 August 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com Abstract The Cacna1a gene encodes the α1A subunit of voltage-gated CaV2.1 Ca2+ channels that are involved in neurotransmission at central synapses. CaV2.1-α1-knockout (α1KO) mice, which lack CaV2.1 channels in all neurons, have a very severe phenotype of cerebellar ataxia and dystonia, and usually die around postnatal day 20. This early lethality, combined with the wide expression of CaV2.1 channels throughout the cerebellar cortex and Boyan Todorov and Lieke Kros equally contributed to this work. Electronic supplementary material The online version of this article (doi:10.1007/s12311-011-0302-1) contains supplementary material, which is available to authorized users. B. Todorov : R. Shyti : R. R. Frants : A. M. J. M. van den Maagdenberg (*) Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands e-mail: maagdenberg@lumc.nl L. Kros : P. Plak : E. D. Haasdijk : F. E. Hoebeek : C. I. De Zeeuw (*) Department of Neuroscience, Erasmus MC, Rotterdam, The Netherlands e-mail: c.dezeeuw@erasmusmc.nl R. S. Raike : E. J. Hess Department of Pharmacology and Neurology, Emory University School of Medicine, Atlanta, GA, USA C. I. De Zeeuw Netherlands Institute for Neuroscience, Royal Dutch Academy for Sciences (KNAW), Amsterdam, The Netherlands A. M. J. M. van den Maagdenberg Department of Neurology, Leiden University Medical Centre, Leiden, The Netherlands nuclei, prohibited determination of the contribution of particular cerebellar cell types to the development of the severe neurobiological phenotype in Cacna1a mutant mice. Here, we crossed conditional Cacna1a mice with transgenic mice expressing Cre recombinase, driven by the Purkinje cell-specific Pcp2 promoter, to specifically ablate the CaV2.1-α1A subunit and thereby CaV2.1 channels in Purkinje cells. Purkinje cell CaV2.1-α1A-knockout (PCα1KO) mice aged without difficulties, rescuing the lethal phenotype seen in α1KO mice. PCα1KO mice exhibited cerebellar ataxia starting around P12, much earlier than the first signs of progressive Purkinje cell loss, which appears in these mice between P30 and P45. Secondary cell loss was observed in the granular and molecular layers of the cerebellum and the volume of all individual cerebellar nuclei was reduced. In this mouse model with a cell type-specific ablation of CaV2.1 channels, we show that ablation of CaV2.1 channels restricted to Purkinje cells is sufficient to cause cerebellar ataxia. We demonstrate that spatial ablation of CaV2.1 channels may help in unraveling mechanisms of human disease. Keywords P/Q-type Ca2+ channels . Conditional . Cell-specific knockout . Cacna1a . Ataxia Introduction CaV2.1 Ca2+ channels are plasma membrane multimeric protein complexes that play an important role in neuro- transmitter release at most central brain synapses [1]. CaV2.1 channels are characterized by the presence of the pore-forming α1A subunit that is encoded by the Cacna1a gene and are widely expressed throughout the nervous system [2, 3]. CaV2.1-α1A-knockout (α1KO) mice that lack