Oxytocin signaling and social phenotype in a Williams-Beuren syndrome mouse model

Williams-Beuren syndrome (WBS) is a rare genetic syndrome caused by hemizygous deletions involving 25-30 genes on chromosome 7. In addition to craniofacial abnormalities, cardiovascular disease, endocrine disturbance, cognitive impairment and visuo-spatial deficits, a common feature of WBS patients is a hyper-social personality usually associated to inappropriate social behaviour, that make them socially vulnerable. Although this syndrome is manageable through assistance programs and pharmacological treatment of the co-morbidities (e.g. hypertension, ADHD, anxiety), in the last decades it has become a model for understanding neurobiological, genetic and neuroendocrine bases of social behaviour and social cognition. Several mouse models of the syndrome have been generated through the years, but the CD mouse model is the only one that most reliably mimics the deletion found in human patients. In the first part of this project, we provided a further characterization of the social-cognitive phenotype of the CD mouse model performing five different behavioral tasks to investigate sociability and emotion discrimination ability. We consistently noticed a higher total time spent in social interaction compared to WT, suggesting that hyper-sociability is well recapitulated in CD mice. On the second part, since oxytocin is known to be crucial in regulating social behaviour by acting centrally, we investigated the oxytocinergic system in CD mice brain through in situ hybridization. Specifically, we examined the expression of oxytocin receptor (OXTR) in SST+ neurons of the mPFC, a neuronal subpopulation involved in emotion discrimination, and the activation of oxytocinergic neurons in PVN. While we observed no differences in the level of SST+/OXTR co-localization between WT and CD mice, we detected a tendency toward a diminished density of SST+ cells in mPFC of CD mice, which could contribute to altering emotional processing. Moreover, our data obtained from ISH performed on PVN region suggests that the activation levels of oxytocin-producing neurons, as well as other neuronal subpopulations in PVN, may differ between WT and CD mice. On the final part, we presented our preliminary results from optogenetic stimulation of oxytocin projections in PrL cortex of WT mice during Emotion Discrimination Test (EDT). This was a pilot experiment, and we cannot draw conclusions due to problems with the virus we used as control treatment. Nonetheless, these results were useful to guide the choice of a different viral strategy. Once we optimize our strategy, the same experiment will be repeated in WT as well as in CD mice to investigate how the manipulation of oxytocinergic circuits affects their socio-cognitive behaviour. Taken together, our findings lay the groundwork for further exploration of the oxytocinergic system in the brain, and for its potential as pharmacological target for treatment of social cognitive deficits associated to Williams-Beuren syndrome and many other psychiatric conditions.