Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

The etiological complexity of psychiatric disorders arises from the dynamic interplay between genetic and environmental vulnerabilities. Among the environmental components, early-life adversities (ELA) are a major risk-factors for developing a psychiatric disorder. Yet, the mechanistic interaction between ELA and genetic vulnerability contributing to psychopathology is poorly understood. To fill this gap, we took advantage of the ideally controlled conditions of a pre-clinical approach. In this study we raised a mouse model with genetic predisposition to multiple psychiatric disorders (autism spectrum, schizophrenia, bipolar disorder), the Cntnap2 +/- mouse, with limited bedding and nesting (LBN), a well-established paradigm to induce early-life stress in rodents. These mice were compared to LBN-raised Cntnap2 +/+ littermates, as well as parallel groups of Cntnap2 +/+ and Cntnap2 +/- raised in standard conditions. Using a battery for behavioral phenotyping we show that ELA shapes non-overlapping phenotypic landscapes based on genetic predisposition. Specifically, we found that LBN-raised Cntnap2 +/- mice develop a perseverative risk-taking behavior in the elevated plus maze and that this behavior is highly predictive of their success in the social interaction, assessed with the 3-chamber test. This finding suggests that the intrusion of anxiety into the social behavioral domain contributes to extreme gain- or loss-of function in social interaction, resembling a bipolar-like phenotype. Finally, we show that LBN promotes synaptic hypertrophy in the basolateral nucleus of the amygdala, but only in Cntnap2 +/- raised in LBN this condition was found in combination with microglia abnormalities. We conclude that the interplay between ELA and Cntnap2 haploinsufficiency exacerbates bipolar-like behaviors in mice, and that this may be consequence of deficient synaptic homeostasis in the basolateral amygdala.