Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates transcripts important for anxiolytic-like behavior

We previously demonstrated that sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) prevents reductions in sociability normally caused by stress. S1PR3 is a ubiquitously expressed G-protein coupled receptor that regulates immune system function, although its regulation of other biological processes is not well understood. Pharmacological activators of S1PR3 might provide important insights for understanding the neural substrates underlying sociability. Here we show that in mice, systemic injections of an S1PR3-specific agonist, CYM5541, promotes sociability in males and females whereas an S1PR3-specific antagonist, CAY10444, increases amygdala activation and increases social avoidance, particularly in females. S1PR3 expression is increased in the mPFC and dentate gyrus of females compared to males. RNA sequencing in the mPFC reveals that S1PR3 activation alters the expression of transcripts related to immune function, neurotransmission, transmembrane ion transport, and intracellular signaling. This work provides evidence that S1PR3 agonists, which have classically been used as immune modulators, might also be used to promote social behavior and, potentially, relieve symptoms of social anxiety. S1PR3 might be an important hub gene for mitigating maladaptive effects of stress as it reduces inflammatory processes, increases transcripts linked to anxiolytic neurotransmission, and promotes social behavior.