22q11.2 microdeletion is currently considered as the highest genetic-based vulnerability factor for neuropsychiatric disorders. Indeed, children carrying 22q11.2 microdeletion face an increased risk for developing autism spectrum disorder (16%), attention deficit hyperactivity disorder (16%), anxiety disorders (25%) and schizophrenia (41%) at adulthood. Accordingly, 22q11.2DS patients present a patchwork of heavy psychiatric disabilities, that might result from alterations in the development of brain trajectories relevant to normal brain functioning. In particular, while there is an impairment in motor/speech delays, learning abilities, attention, executive function, working memory, visual spatial abilities and motor skills, the most debilitating symptoms of 22q11.2DS are deficits in face memory and social cognition. Considering the current lack of treatment to alleviate the negative symptoms (including social interaction deficits) of schizophrenia, which remains the most frequent neuropsychiatric disorder related to 22q11.2DS defining a proper therapeutic strategy to cure social impairment should be considered one of the utmost challenges in the fight against 22q11.2DS. Notably, the identification of the neuroanatomical substrates of social deficits in 22q11.2DS appears critical to develop effective therapies. In this context, the developmental trajectories of the oxytocin (OT) and dopamine (DA) systems in normal and 22q11.2DS brains might offer very promising prospects for the identification of pharmacological targets for the therapeutic care of 22q11.2DS social deficits. In the present project, behavioral exploration (social habituation/dishabituation, sociability, social novelty, emotion recognition tests…etc) demonstrated the existence of specific deficits in the social profile of LgDel+/- mice compared to their wild-type littermates. Molecular investigations achieved so far indicate an altered expression of molecular markers of the GABA and glutamate systems within the social brain circuitry of LgDel+/- mice, some of which being reversed by the perinatal treatment with oxytocin. In addition, the project’s outcomes outlined that some components of the dopaminergic system are impaired in subcortical brain regions receiving direct inputs from the mPFC. These latter findings provide mechanistic insights into the dopaminergic impairments observed, within the framework of an international collaboration, in patients bearing 22q11 genetic variation. Altogether the results achieved so far allow a better definition of the social disabilities and likely-related molecular imbalance occurring in 22q11 genetic variation. Furthermore, these findings provide interesting insights into the therapeutic potential of early oxytocin treatment in 22q11 deletion syndrome to prevent the development of « social brain » imbalance and ultimately, social deficits at adulthood. Besides the scientific impact, the project substantially impacted the researcher’s career. The new scientific and soft skills acquired over the course of the project increased technical competence and enhanced the preparation of the researcher for an independent career. The communication and dissemination activities resulting from the project contributed to the improvement of the researcher’s track record. Overall, the project strengthened the researcher’s motivation and prospects to apply for researcher positions.
