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

Abstract

As cross‐disorder risk gene, CACNA1C is implicated in the etiology of all major neuropsychiatric disorders characterized by deficits in social behavior and communication and there is evidence for sex‐dependent influences of single‐nucleotide polymorphisms within CACNA1C on diagnosis, course, and recovery in humans. In this study, we aimed, therefore, at further exploring the role of Cacna1c in regulating behavioral phenotypes, focusing on sex‐specific differences in social behavior and communication during the critical developmental period of adolescence in rats. Specifically, we compared rough‐and‐tumble play, concomitant emission of pro‐social 50‐kHz ultrasonic vocalizations, and social approach behavior in response to playback of 50‐kHz ultrasonic vocalizations between constitutive heterozygous Cacna1c +/− females and wildtype Cacna1c +/+ littermate controls, and contrasted present female findings to data previously reported in males. Our results show for the first time that partial depletion of Cacna1c leads to sex‐dependent alterations in social behavior and communication in rats. In females, Cacna1c haploinsufficiency led to hypermasculinization, with rough‐and‐tumble play behavior, in general, and pinning behavior, in particular, being even higher than in males without affecting concomitant 50‐kHz ultrasonic vocalizations. In males, in contrast, rough‐and‐tumble play behavior was not altered, yet emission of 50‐kHz ultrasonic vocalizations was diminished following partial Cacna1c depletion. The behavioral responses elicited by playback of 50‐kHz ultrasonic vocalizations were reduced upon partial Cacna1c depletion in both sexes. It thus can be concluded that Cacna1c plays a prominent sex‐dependent role in regulating juvenile rat social play behavior and pro‐social 50‐kHz ultrasonic communication with relevance to sex‐specific effects seen in neuropsychiatric disorders.

Translational outcomes in a full gene deletion of ubiquitin protein ligase E3A rat model of Angelman syndrome

“…3a genotype F (1, 68) = 2.548, p > 0.05). As shown by our laboratory and others previously 15,[18][19][20][21][22] , a striking increase in social exploratory behavior (i.e., distance traveled) was observed in response to playback of pro-social 50-kHz USV. Distance traveled increased in response to playback of 50- Ube3a m−/p+ rats again exhibited normal horizontal activity, e significantly lower vertical activity, and f normal center time.…”

“…In contrast to the wildtype, Ube3a m−/p+ subjects failed to show a strong, sustained response to hearing the cue and only spent significantly more time on the proximal arms during the time period the audio cue was "on". This was an unusual display of social behavior as there should be (1) a clear behavioral preference for the proximal versus distal arms and (2) sustained attempts to locate the source of the emission, as previously reported across genetic models and groups 12,15,18,20,39 . The behavioral alterations displayed by Ube3a m−/p+ rats in response to pro-social 50-kHz USV were clear and substantially more prominent than the social communication deficits seen in other recently developed rat models relevant to autism, including Shank3 15 and Cacna1c 18,19 .…”

“…This was an unusual display of social behavior as there should be (1) a clear behavioral preference for the proximal versus distal arms and (2) sustained attempts to locate the source of the emission, as previously reported across genetic models and groups 12,15,18,20,39 . The behavioral alterations displayed by Ube3a m−/p+ rats in response to pro-social 50-kHz USV were clear and substantially more prominent than the social communication deficits seen in other recently developed rat models relevant to autism, including Shank3 15 and Cacna1c 18,19 . While individuals with AS are typically thought of as being highly social, and/or uninhibited socially, with excessive smiling being a hallmark behavioral feature in AS, aberrant social behavior is considered a core phenotypic trait.…”

“…On PND 4,6,8,10,12,14,16,and 18, developmental milestones were assessed as described previously 73 . Negative geotaxis was tested by placing each pup on an angled screen (45 degrees) facing downwards and measuring the time taken to make a complete 180 degree turn up the screen.…”

Genetic Adaptation in New York City Rats

“…Thus, rat behavioral phenotypes associated with anxiety (such as anti-predator responses or responses to novel stimuli) are promising areas for future investigation. CACNA1C has also been demonstrated to influence social behavior and communication in rats [55]. CACNA1C and multiple other top-scoring genes like FGF12, EPHA3 and CHAT ( Table S4 ) may also affect locomotion in rodents [56, 57].…”