Repeat investigation during social preference behavior is suppressed in male mice with prefrontal cortex cacna1c (Ca_v1.2)-deficiency through the dysregulation of neural dynamics

Impairments in social behavior are observed in a range of neuropsychiatric disorders and several lines of evidence have demonstrated that dysfunction of the prefrontal cortex (PFC) plays a central role in social deficits. We have previously shown that loss of neuropsychiatric risk gene Cacna1c that codes for the Ca_v1.2 isoform of L-type calcium channels (LTCCs) in the PFC result in impaired sociability as tested using the three-chamber social approach test. In this study we aimed to further characterize the nature of the social deficit associated with a reduction in PFC Ca_v1.2 channels (Cav1.2^PFCKO mice) by testing male mice in a range of social and nonsocial tests while examining PFC neural activity using in vivo GCaMP6s fiber photometry. We found that during the first investigation of the social and non-social stimulus in the three-chamber test, both Ca_v1.2^PFCKO male mice and Ca_v1.2^PFCGFP controls spent significantly more time with the social stimulus compared to a non-social object. In contrast, during repeat investigations while Ca_v1.2^PFCWT mice continued to spend more time with the social stimulus, Ca_v1.2^PFCKO mice spent equal amount of time with both social and non-social stimuli. Neural activity recordings paralleled social behavior with increase in PFC population activity in Ca_v1.2^PFCWT mice during first and repeat investigations, which was predictive of social preference behavior. In Ca_v1.2^PFCKO mice, there was an increase in PFC activity during first social investigation but not during repeat investigations. These behavioral and neural differences were not observed during a reciprocal social interaction test nor during a forced alternation novelty test. To evaluate a potential deficit in reward-related processes, we tested mice in a three-chamber test wherein the social stimulus was replaced by food. Behavioral testing revealed that both Ca_v1.2^PFCWT and Ca_v1.2^PFCKO mice showed a preference for food over object with significantly greater preference during repeat investigation. Interestingly, there was no increase in PFC activity when Ca_v1.2^PFCWT or Ca_v1.2^PFCKO first investigated the food however activity significantly increased in Ca_v1.2^PFCWT mice during repeat investigations of the food. This was not observed in Ca_v1.2^PFCKO mice. In summary, a reduction in Ca_v1.2 channels in the PFC suppresses the development of a sustained social preference in mice that is associated with lack of PFC neuronal population activity that may be related to deficits in social reward.