Sex-Specific Effects of Cacna1c Haploinsufficiency on Social Behavior, Ultrasonic Communication, and Cognition in Rats

The risk gene CACNA1C encodes for the α1C subunit of the L-type voltage-gated Ca2+ channel, known as Cav1.2. Genome wide association studies have implicated CACNA1C in neuropsychiatric disorders, such as major depression, bipolar disorder, schizophrenia, and autism spectrum disorder. Importantly, social behavior and communication deficits are persistent in each disorder with added cognitive impairments similarly being present. Several studies in humans and mouse models have indicated that Cav1.2 expression levels are associated with alterations in sociability and cognition. Rat models provide an ideal translational tool to determine underlying disease pathomechanisms, due in part to their highly gregarious nature emerging early in life, thus, creating a practical means to study the development of social behavior and communication. Using a newly developed Cacna1c rat model, this dissertation aimed at exploring the role Cacna1c plays in social behavior and communication in juvenile rats, as well as the association with cognitive impairments in adulthood. Detailed practical assessment for juvenile behavior and ultrasonic vocalizations (USV) outline social play (Review I) and USV playback (Review II) as pertinent paradigms to assess alterations in social behavior and communication with relevance to neuropsychiatric disorders. Results indicate that deficits in 50-kHz USV were evident in male haploinsufficient Cacna1c rats in the sender and receiver (Study I). Cacna1c haploinsufficiency in females resulted in abnormal social play behaviour and minor deficits in response to 50-kHz USV playback (Study II). Moreover, Cacna1c rats appear to show normal, and in some cases above normal, cognitive abilities, albeit with a slight reduction in cognitive flexibility in haploinsufficient Cacna1c males (Study III). Together, these findings further extend the notion that Cav1.2 expression levels may be associated with alterations in social behavior, communication, and cognitive abilities in a sex-dependent manner, with important bearings on neuropsychiatric disorders