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.