Repeat investigation during social preference behavior is suppressed in male mice with prefrontal cortex cacna1c (Ca v 1.2)-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 that codes for the Ca 1.2 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 1.2 channels (Cav1.2 mice) by testing male mice in a range of social and non-social tests while examining PFC neural activity using GCaMP6s fiber photometry. We found that during the first investigation of the social and non-social stimulus in the three-chamber test, both Ca 1.2 male mice and Ca 1.2 controls spent significantly more time with the social stimulus compared to a non-social object. In contrast, during repeat investigations while Ca 1.2 mice continued to spend more time with the social stimulus, Ca 1.2 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 1.2 mice during first and repeat investigations, which was predictive of social preference behavior. In Ca 1.2 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 1.2 and Ca 1.2 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 1.2 or Ca 1.2 first investigated the food however activity significantly increased in Ca 1.2 mice during repeat investigations of the food. This was not observed in Ca 1.2 mice. In summary, a reduction in Ca 1.2 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.