Neuronal deletion of Ca(V)1.2 is associated with sex-specific behavioral phenotypes in mice

The gene CACNA1C, which encodes the pore forming subunit of the L-type calcium channel Ca(V)1.2, 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 Ca(V)1.2 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 Ca(V)1.2. 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 Ca(V)1.2 (neuronal Ca(V)1.2 cKO) using Syn1-Cre-mediated conditional deletion. We found that neuronal Ca(V)1.2 cKO mice have normal baseline locomotor function but female cKO mice display impaired motor performance learning. Male neuronal Ca(V)1.2 cKO display impaired startle response with intact pre-pulse inhibition. Male neuronal Ca(V)1.2 cKO mice did not display normal social preference, whereas female neuronal Ca(V)1.2 cKO mice did. Neuronal Ca(V)1.2 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 Ca(V)1.2 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 Ca(V)1.2.