Conditional inactivation of theCacna1a gene in transgenic mice

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Abstract
Cav2.1 (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 α1 subunit of Cav2.1 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 Cav2.1 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 Cav2.1 channel‐mediated neurotransmission that was accompanied by a compensatory upregulation of Cav2.3 (R‐type) channels at this synapse. Pharmacological inhibition of Cav2.1 channels is possible, but the contributing cell‐types and time windows relevant to the different Cav2.1‐related neurological disorders can only be reliably determined using Cacna1a conditional mice. genesis 44:589–594, 2006.