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

Theresa M Kisko,Markus Wöhr,Stephanie H Witt,Marcella Rietschel,Moria D Braun,Susanne Michels,Carsten Culmsee,Rainer K W Schwarting

doi:10.1242/dmm.034116

Abstract

ABSTRACTThe 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.This article has an associated First Person interview with the first author of the paper.

Highlights

Most cases arise from a G406R CACNA1C missense mutation (Splawski et al, 2004) and a Timothy syndrome (TS) mouse model carrying the G406R replacement in Cav1.2 was reported to display April disorder (ASD)-related behavioral phenotypes (Bader et al, 2011)
Behavioral phenotypes with relevance for socio-affective communication deficits in ASD, bipolar disorder (BPD) and SCZ have not been assessed in rats with genetic modifications targeting Cacna1c until now, and available mouse studies almost exclusively focused on adult mice (Kabir et al, 2016), with no data being available on the role of Cacna1c in regulating socio-affective communication during the critical developmental period of adolescence
Our results show for the first time that Cacna1c deletion leads to pro-social 50-kHz ultrasonic communication deficits and may suggest reduced incentive salience of social contact in Cacna1c haploinsufficient rats

Summary

Introduction

The cross-disorder risk gene CACNA1C is strongly implicated in multiple neuropsychiatric disorders, including autism spectrum. Rats are highly gregarious animals with a rich and complex social behavior repertoire. They display cooperation, reciprocity and mutual reward preferences (Hernandez-Lallement et al, 2015), linked to empathy-driven helping behavior (Ben-Ami Bartal et al, 2011). The complex nature of social play involves coordination and integration of behavior and communication, requiring numerous neural systems (Vanderschuren et al, 2016), and individual rough-and-tumble play components, such as pinning, wrestling and chasing, were found to be selectively affected by genetic (Homberg et al, 2007), prenatal (Raza et al, 2015), pharmacological (Vanderschuren et al, 1995) and brain (Schneider and Koch, 2005) manipulations

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Conclusion