Purkinje Cell-Specific Ablation of Ca(V)2.1 Channels is Sufficient to Cause Cerebellar Ataxia in Mice

B Todorov, Lieke Kros, R Shyti, Petra Plak, Elize Haasdijk, RS Raike, RR Frants, EJ Hess, Freek Hoebeek, Chris de Zeeuw, AMJM Maagdenberg

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Abstract

The Cacna1a gene encodes the alpha(1A) subunit of voltage-gated Ca(V)2.1 Ca2+ channels that are involved in neurotransmission at central synapses. Ca(V)2.1-alpha(1)-knockout (alpha 1KO) mice, which lack Ca(V)2.1 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 Ca(V)2.1 channels throughout the cerebellar cortex and 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 Ca(V)2.1-alpha(1A) subunit and thereby Ca(V)2.1 channels in Purkinje cells. Purkinje cell Ca(V)2.1-alpha(1A)-knockout (PC alpha 1KO) mice aged without difficulties, rescuing the lethal phenotype seen in alpha 1KO mice. PC alpha 1KO 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 Ca(V)2.1 channels, we show that ablation of Ca(V)2.1 channels restricted to Purkinje cells is sufficient to cause cerebellar ataxia. We demonstrate that spatial ablation of Ca(V)2.1 channels may help in unraveling mechanisms of human disease.
Original languageUndefined/Unknown
Pages (from-to)246-258
Number of pages13
JournalThe Cerebellum
Volume11
Issue number1
DOIs
Publication statusPublished - 2012

Research programs

  • EMC ONWAR-01-94-01

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