Phosphorylation-dependent positive feedback on the oxytocin receptor through the kinase PKD1 contributes to long-term social memory.

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 Ser in OXTR was phosphorylated by protein kinase D1 (PKD1). Neuronal Ca 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 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 G 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.