Cacna1c haploinsufficiency leads to pro-social 50-kHz ultrasonic communication deficits in rats

Abstract

The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum disorder (ASD), bipolar disorder (BPD) and schizophrenia (SCZ), with deficits in social functioning being common for all major neuropsychiatric disorders. In the present study, we explored the role of Cacna1c in regulating disorder-relevant behavioral phenotypes, focusing on socio-affective communication after weaning during the critical developmental period of adolescence in rats. To this aim, we used a newly developed genetic Cacna1c rat model and applied a truly reciprocal approach for studying communication through ultrasonic vocalizations, including both sender and receiver. Our results show that a deletion of Cacna1c leads to deficits in social behavior and pro-social 50-kHz ultrasonic communication in rats. Reduced levels of 50-kHz ultrasonic vocalizations emitted during rough-and-tumble play may suggest that Cacna1c haploinsufficient rats derive less reward from playful social interactions. Besides the emission of fewer 50-kHz ultrasonic vocalizations in the sender, Cacna1c deletion reduced social approach behavior elicited by playback of 50-kHz ultrasonic vocalizations. This indicates that Cacna1c haploinsufficiency has detrimental effects on 50-kHz ultrasonic communication in both sender and receiver. Together, these data suggest that Cacna1c plays a prominent role in regulating socio-affective communication in rats with relevance for ASD, BPD and SCZ..

Sex‐dependent effects of Cacna1c haploinsufficiency on juvenile social play behavior and pro‐social 50‐kHz ultrasonic communication in rats

“…55 Acoustic communication is another prominent element of the rat social behavior repertoire. 45 Despite no alterations in rough-andtumble play behavior, 50-kHz USV were consistently reduced across all play sessions in male Cacna1c haploinsufficient rats, possibly reflecting reduced liking 69 of playful interactions. [56][57][58] Converging evidence from selective breeding, surgical devocalization, and sound playback studies supports the notion that such USV serve as situation-dependent socio-affective signals, with specific USV types fulfilling distinct communicative functions.…”

“…45 Despite no alterations in rough-andtumble play behavior, 50-kHz USV were consistently reduced across all play sessions in male Cacna1c haploinsufficient rats, possibly reflecting reduced liking 69 of playful interactions. 80 In fact, in our recent study in male Cacna1c haploinsufficient rats, 45 we found that a decrease in Ca v 1.2 expression levels not only leads to impairments in ultrasonic communication in the sender but also in the recipient rat. [72][73][74] As repeatedly demonstrated in playback studies, 50-kHz USV serve important pro-social communicative functions.…”

“…In fact, in a broad range of social situations characterized by high emotional valence, rats emit whistle-like calls above the human hearing range, so-called ultrasonic vocalizations (USV). This reduction was paralleled by alterations in the prevalence of subtype variations of 50-kHz USV, 45 including, for example, FLAT or TRILL 50-kHz USV, 62,70,71 previously associated with distinct affective states and communicative functions. Specifically, 22-kHz USV occur in aversive situations, such as the exposure to predators, fighting, and fear learning, and are thought to reflect a negative affective state of the sender.…”

“…12,39,40 A common feature of all major neuropsychiatric disorders is reduced social functioning. 45 As highly gregarious animals living in large groups characterized by prominent social hierarchies, rats display a rich and complex social behavior repertoire. Rats are a useful model system to study neurobiological mechanisms underlying deficits in social functioning with relevance to neuropsychiatric disorders in humans 43,44 and in a recent study we obtained evidence for social behavior and communication deficits in male Cacna1c haploinsufficient rats.…”

“…To this aim, we took advantage of our previously developed genetic Cacna1c rat model 45 and applied behavioral assays specifically designed to truly capture the interactive and reciprocal nature of social encounters. To this aim, we took advantage of our previously developed genetic Cacna1c rat model 45 and applied behavioral assays specifically designed to truly capture the interactive and reciprocal nature of social encounters.…”