The human neuropsychiatric risk gene Drd2is necessary for social functioning across evolutionary distant species

The Drd2gene, encoding the dopamine D2receptor (D2R), was recently indicated as a potential target in the etiology of lowered sociability (i.e., social withdrawal), a symptom of several neuropsychiatric disorders such as Schizophrenia and Major Depression. Many animal species show social withdrawal in response to stimuli, including the vinegar fly Drosophila melanogasterand mice, which also share most human disease-related genes. Here we will test for causality between Drd2and sociability and for its evolutionary conserved function in these two distant species, as well as assess its mechanism as a potential therapeutic target. During behavioral observations in groups of freely interacting D. melanogaster, Drd2homologue mutant showed decreased social interactions and locomotor activity. After confirming Drd2’s social effects in flies, conditional transgenic mice lacking Drd2in dopaminergic cells (autoreceptor KO) or in serotonergic cells (heteroreceptor KO) were studied in semi-natural environments, where they could freely interact. Autoreceptor KOs showed increased sociability, but reduced activity, while no overall effect of Drd2deletion was observed in heteroreceptor KOs. To determine acute effects of D2R signaling on sociability, we also showed that a direct intervention with the D2R agonist Sumanirole decreased sociability in wild type mice, while the antagonist showed no effects. Using a computational ethological approach, this study demonstrates that Drd2regulates sociability across evolutionary distant species, and that activation of the mammalian D2R autoreceptor, in particular, is necessary for social functioning.