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

Chelini, G.; Fortunato-Asquini, T.; Cerilli, E.; Monsorno, K.; Catena, B.; Dall'O', G. M.; Paolicelli, R. C.; Bozzi, Y.

doi:10.1101/2024.04.18.589746

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bioRxiv · 10.1101/2024.04.18.589746

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

Chelini, G.·Fortunato-Asquini, T.·Cerilli, E.·Monsorno, K.·Catena, B.·Dall'O', G. M.·Paolicelli, R. C.·Bozzi, Y.

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Abstract

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.

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Chelini, G., Fortunato-Asquini, T., Cerilli, E., Monsorno, K., Catena, B., Dall'O', G. M., Paolicelli, R. C., Bozzi, Y.. 2024-04-18. Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2. https://doi.org/10.1101/2024.04.18.589746

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