LAUSR

Social memory enables one to recognize and distinguish specific individuals. It is fundamental to social behaviors that can be mediated by the oxytocin receptor (OXTR), such as forming relationships. We investigated the molecular regulation and function of OXTR in animal behavior involving social memory. We found that Ser261 in OXTR was phosphorylated by protein kinase D1 (PKD1). Neuronal Ca2+ signaling and behavior analyses revealed that rats expressing a mutated form of OXTR that cannot be phosphorylated at this residue (OXTR S261A) in the medial amygdala (MeA) exhibited impaired long-term social memory (LTSM). Blocking the phosphorylation of wild-type OXTR in the MeA using an interfering peptide in rats or through conditional knockout of Pkd1 in mice reduced social memory retention, whereas expression of a phosphomimetic mutant of OXTR rescued it. In HEK293A cells, the PKD1-mediated phosphorylation of OXTR promoted its binding to Gq protein and, in turn, OXTR-mediated phosphorylation of PKD1, indicating a positive feedback loop. In addition, OXTR with a single-nucleotide polymorphism found in humans (rs200362197), which has a mutation in the conserved recognition region in the PKD1 phosphorylation site, showed impaired activation and signaling in vitro and in HEK293A cells similar to that of the S216A mutant. Our findings describe a phosphoregulatory loop for OXTR and its critical role in social behavior that might be further explored in associated disorders. Description A positive feedback loop that stimulates oxytocin receptor activity helps rodents remember each other. Familiarity feedback Social memory enables the recognition of others and the formation and maintenance of relationships and thus regulates social behaviors. It is in part supported by the bonding hormone oxytocin. Wang et al. found that an oxytocin receptor–dependent positive feedback loop contributes to long-term social memory in rodents. Reciprocal phosphorylation between the receptor and the kinase PKD1 promoted downstream oxytocin receptor signaling in cultured cells. Rodents in which this loop was disrupted in the medial amygdala of the brain showed behaviors and neuronal activity that indicated impaired recognition of familiar cage mates. The findings provide molecular and physiological insight on how oxytocin signaling promotes social memory.