Functional compensation by other voltage-gated Ca2+ channels in mouse basal forebrain neurons with CaV2.1 mutations

Tottering (tg/tg) and leaner (tgla/tgla) mutant mice exhibit distinct mutations in the gene encoding the voltage-activated Ca2+ channel α1A subunit (CACNA1A), the pore-forming subunit of the CaV2.1 (P/Q type) Ca2+ channels. These mice exhibit absence seizures and deficiencies in motor control and other functions. Previous work in cerebellar Purkinje neurons has shown that these mutations cause dramatic reductions in calcium channel function. Because Purkinje cell somata primarily express the CaV2.1 channels, the general decrease in CaV2.1 channel function is observed as a profound decrease in whole-cell current. In contrast to Purkinje cells, basal forebrain (BF) neurons express all of the Ca2+ channel α1 subunits, with CaV2.1 contributing approximately 30% to the whole-cell current in wild-type (+/+) mice. Here, we show that whole-cell Ba2+ current densities in BF neurons are not reduced in the mutant genotypes despite a reduction in the CaV2.1 contribution. By blocking the different Ca2+ channel subtypes with specific pharmacological agents, we found a significant increase in the proportion of CaV1 Ca2+ current in mutant phenotypes. There was no change in tissue mRNA expression of calcium channel subtypes CaV2.1, CaV2.2, CaV1.2, CaV1.3, and CaV2.3 in the tottering and leaner mutant mice. These results suggest that CaV1 channels may functionally upregulate to compensate for reduced CaV2.1 function in the mutants without an increase in Cav1 message. Single-cell reverse transcription polymerase chain reaction (RT-PCR) experiments in a subset of sampled neurons revealed that ∼90% of the cells could be considered cholinergic based on choline acetyltransferase (ChAT) mRNA expression.