Sex-dependent effects of Cacna1c haploinsufficiency on behavioral inhibition evoked by conspecific alarm signals in rats

Deficits in processing social signals leads to reduced social functioning and is typically associated with neuropsychiatric disorders, including autism spectrum disorder, schizophrenia, and major depressive disorder. The cross-disorder risk gene CACNA1C is implicated in the etiology of all of these disorders and single-nucleotide polymorphisms within CACNA1C are ranked among the best replicated and most robust genetic findings from genome-wide association studies in psychiatry. Rats are highly social, live in large social groups, and communicate through ultrasonic vocalizations (USV), with low-frequency 22-kHz USV emitted in dangerous and often life-threating situations, such as predator exposure, serving an alarming function. In the present study, we applied an alarm 22-kHz USV playback paradigm to investigate the role of Cacna1c in socio-affective information processing in rats. Specifically, we assessed behavioral inhibition evoked by 22-kHz USV in constitutive heterozygous Cacna1c(+/+) females and males, as compared to wildtype Cacna1c(+/+) littermate controls. To probe specificity, two sets of alarm 22-kHz USV were presented, i.e. 22-kHz USV elicited by predator urine exposure and 22-kHz USV emitted during a retention test on learned fear, together with acoustic control stimuli. Our results show that behavioral inhibition evoked by playback of alarm 22-kHz USV is robust and occurs in response to both sets, yet is modulated by Cacna1c in a sex-dependent manner. In male but not female rats, Cacna1c haploinsufficiency led to less pronounced and less specific behavioral inhibition, supporting the idea that Cacna1c haploinsufficiency results in a lower motivation and/or diminished capability to display appropriate responses to important socio-affective communication signals.