Neuronal deletion of CaV1.2 is associated with sex-specific behavioral phenotypes in mice

Abstract The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel CaV1.2, is associated with increased risk for neuropsychiatric disorders including schizophrenia, autism spectrum disorder, major depression, and bipolar disorder. Previous rodent work identified that loss or reduction of CaV1.2 results in cognitive, affective, and motor deficits. Most previous work has either included non-neuronal cell populations (haploinsufficient and Nestin-Cre) or investigated a discrete neuronal cell population (e.g. CaMKII-Cre, Drd1-Cre), but few studies have examined the effects of more broad neuron-specific deletion of CaV1.2. Additionally, most of these studies did not evaluate for sex-specific effects or used only male animals. Here, we sought to clarify whether there are sex-specific behavioral consequences of neuron-specific deletion of CaV1.2 (neuronal CaV1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal CaV1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal CaV1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal CaV1.2 cKO mice did not display normal social preference, whereas female neuronal CaV1.2 cKO mice did. Neuronal CaV1.2 cKO mice displayed impaired associative learning in both sexes, as well as normal anxiety-like behavior and hedonic capacity. We conclude that deletion of neuronal CaV1.2 alters motor performance, acoustic startle reflex, and social behaviors in a sex-specific manner, while associative learning deficits generalize across sexes. Our data provide evidence for both sex-specific and sex-independent phenotypes related to neuronal expression of CaV1.2.