2024/12/03 by Jose Castro-Vildosola, Chris-Ann Bryan, Nasira Tajamal +12 · 1 citation
Biochemistry, Genetics and Molecular Biology · Neuroscience · #Circadian rhythm and melatonin #Neuroinflammation and Neurodegeneration Mechanisms #Sphingolipid Metabolism and Signaling
paper · doi:10.1016/j.bbi.2024.12.001
openalex publication_date 2024/12/03 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/03
• The Sphingosine-1-phosphate receptor 3 (S1PR3) agonist CYM5541 promotes sociability in male and female mice. • The S1PR3 antagonist CAY10444 reduces sociability, with a stronger effect in females. • CAY10444 increases neuronal activity markers in the amygdala. • Pharmacological activation of S1PR3 regulates the expression of genes in the prefrontal cortex that control a wide range of biological processes, including increasing GABAergic neurotransmission and reducing inflammatory processes. 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.