TY - JOUR T1 - Complex interactions between genes and social environment cause phenotypes associated with Autism Spectrum Disorders in mice JF - eneuro JO - eNeuro DO - 10.1523/ENEURO.0124-20.2020 SP - ENEURO.0124-20.2020 AU - Monika Sledziowska AU - Shireene Kalbassi AU - Stéphane J. Baudouin Y1 - 2020/07/15 UR - http://www.eneuro.org/content/early/2020/07/15/ENEURO.0124-20.2020.abstract N2 - The aetiology of Autism Spectrum Disorders (ASD) is a complex combination of genetic and environmental factors. Neuroligin3, a synaptic adhesion protein, and Cytoplasmic FMR1 interacting protein 1 (CYFIP1), a regulator of protein translation and actin polymerisation, are two proteins associated with ASD, that interact in neurons, in vivo. Here, we investigated the role of the Neuroligin3/CYFIP1 pathway in behavioural functioning and synapse formation in mice and found that it contributes to motor learning and synapse formation in males. Similar investigation in female mice revealed an absence of such phenotypes, suggesting that females are protected against mutations affecting this pathway. Previously, we showed that the social environment influences the behaviour of male mice. We extended this finding and found that the transcriptome of wild type mice housed with their mutant littermates, lacking Neuroligin3, differed from the transcriptome of wild type mice housed together. Altogether, these results identify the role of the Neuroligin3/CYFIP1 pathway in male mouse behaviour and highlight its sensitivity to social environment.Significance statement The causes of Autism Spectrum Disorders remain elusive. In this study, we investigate the combined effect of mutations in two genes associated with ASD: Nlgn3 and Cyfip1, and the effect of the social environment, on phenotypes relevant for ASD. We show that when both mutations are present the behaviour can be restored, emphasising the importance of considering gene interactions. We also show sex differences in behaviour, suggesting that female subjects should be included in the studies of ASD. We show that wild type animals can exhibit phenotypes associated with ASD as a result of being housed with their mutant littermates, highlighting the necessity to re-evaluate the use of wild type animals as controls to define phenotypic traits of mouse models. ER -