title: Purkinje cell-specific ablation of Cav2.1 channels is sufficient to cause cerebellar ataxia in mice.
abstract: The Cacna1a gene encodes the α(1A) subunit of voltage-gated Ca(V)2.1 Ca(2+) channels that are involved in neurotransmission at central synapses. Ca(V)2.1-α(1)-knockout (α1KO) 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-α(1A) subunit and thereby Ca(V)2.1 channels in Purkinje cells. Purkinje cell Ca(V)2.1-α(1A)-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 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.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Boyan
authors.initials: B
authors.lastname: Todorov
authors.forename: Lieke
authors.initials: L
authors.lastname: Kros
authors.forename: Reinald
authors.initials: R
authors.lastname: Shyti
authors.forename: Petra
authors.initials: P
authors.lastname: Plak
authors.forename: Elize D
authors.initials: ED
authors.lastname: Haasdijk
authors.forename: Robert S
authors.initials: RS
authors.lastname: Raike
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Ellen J
authors.initials: EJ
authors.lastname: Hess
authors.forename: Freek E
authors.initials: FE
authors.lastname: Hoebeek
authors.forename: Chris I
authors.initials: CI
authors.lastname: De Zeeuw
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000172:deficiency* / Q000235:genetics; D002524:Cerebellar Ataxia / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D002525:Cerebellar Cortex / Q000378:metabolism / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011689:Purkinje Cells / Q000378:metabolism / Q000473:pathology*
chemical_list: D020864:Calcium Channels, N-Type