title: Conditional inactivation of the Cacna1a gene in transgenic mice.
abstract: Ca(v)2.1 (P/Q-type) voltage-gated calcium channels play an important role in neurotransmitter release at many brain synapses and at the neuromuscular junction. Mutations in the CACNA1A gene, encoding the pore forming alpha(1) subunit of Ca(v)2.1 channels, are associated with a wide spectrum of neurological disorders. Here we generated mice with a conditional, floxed, Cacna1a allele without any overt phenotype. Deletion of the floxed Cacna1a allele resulted in ataxia, dystonia, and lethality during the fourth week, a severe phenotype similar to conventional Ca(v)2.1 knockout mice. Although neurotransmitter release at the neuromuscular junction was not affected in the conditional mice, homozygous deletion of the floxed allele caused an ablation of Ca(v)2.1 channel-mediated neurotransmission that was accompanied by a compensatory upregulation of Ca(v)2.3 (R-type) channels at this synapse. Pharmacological inhibition of Ca(v)2.1 channels is possible, but the contributing cell-types and time windows relevant to the different Ca(v)2.1-related neurological disorders can only be reliably determined using Cacna1a conditional mice.
authors.affiliation: Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Boyan
authors.initials: B
authors.lastname: Todorov
authors.forename: Rob C G
authors.initials: RC
authors.lastname: van de Ven
authors.forename: Simon
authors.initials: S
authors.lastname: Kaja
authors.forename: Ludo A M
authors.initials: LA
authors.lastname: Broos
authors.forename: Sjef J
authors.initials: SJ
authors.lastname: Verbeek
authors.forename: Jaap J
authors.initials: JJ
authors.lastname: Plomp
authors.forename: Michel D
authors.initials: MD
authors.lastname: Ferrari
authors.forename: Rune R
authors.initials: RR
authors.lastname: Frants
authors.forename: Arn M J M
authors.initials: AM
authors.lastname: van den Maagdenberg
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type / Q000235:genetics*; D020907:Calcium Channels, Q-Type / Q000235:genetics*; D017931:DNA Primers; D004594:Electrophysiology; D040461:Gene Components; D020868:Gene Silencing; D051379:Mice; D008822:Mice, Transgenic; D009469:Neuromuscular Junction / Q000235:genetics; D018377:Neurotransmitter Agents / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism*; D013569:Synapses / Q000235:genetics
chemical_list: D020864:Calcium Channels, N-Type; D020865:Calcium Channels, P-Type; D020907:Calcium Channels, Q-Type; D017931:DNA Primers; D018377:Neurotransmitter Agents; D012313:RNA