Yun Wang’s group has recently published a paper on Science Signaling titled “Phosphorylation-dependent positive feedback on the oxytocin receptor through the kinase PKD1 contributes to long-term social memory” and demonstrated mechanisms of the posttranslational phosphorylation of OXTR at Ser261 and a positive feedback regulation between OXTR and PKD1, which amplifies OXTR signaling and contributes to LTSM consolidation in the MeA.

　　Abnormal social behavior is associated with various neurological conditions, such as autism spectrum disorder and schizophrenia. Among various types of social behaviors, social memory—the ability to recognize and distinguish specific individuals—is a prerequisite for exhibiting appropriate behaviors. The hormone oxytocin (OXT) and its receptor (OXTR) are widely expressed in brain regions associated with networks that play a major role in regulating social behaviors and emotions. However, the posttranscriptional regulation of OXTR and its functions remains unknown.

　　Our study reveals 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. Additionally, 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.

　　This study provides brain area- and cellular signaling-specific evidence for social memory regulation by the modification of OXTR and new insights into the molecular mechanisms underlying social deficits. Moreover, we have revealed the fine-tune and specific functions of OXTR signaling, these findings may be helpful to identify more efficient therapeutic strategies to applicate the OXT system and to improve social learning and prosocial behaviors.

　　This work was supported by grants from the Ministry of Science and Technology of China (2021ZD0203204 to YW) and grants from the National Natural Science Foundation of China (31530028 to Y.W., 81873738 to C.C., 31720103908 and 81821092 to Y.W.).