TY - JOUR
T1 - Sphingosine-1-phosphate receptor 3 activation promotes sociability and regulates transcripts important for anxiolytic-like behavior
AU - Castro-Vildosola, Jose
AU - Bryan, Chris Ann
AU - Tajamal, Nasira
AU - Jonnalagadda, Sai Anusha
AU - Kasturi, Akhila
AU - Tilly, Jacqueline
AU - Garcia, Isabel
AU - Kumar, Renuka
AU - Fried, Nathan T.
AU - Hala, Tamara
AU - Corbett, Brian F.
N1 - Publisher Copyright: © 2024 The Authors
PY - 2025/2
Y1 - 2025/2
N2 - 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.
AB - 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.
KW - Amygdala
KW - GABA
KW - Inflammatory response
KW - Prefrontal cortex
KW - Sphingosine-1-phosphate receptor 3
KW - Transcriptomics
UR - http://www.scopus.com/inward/record.url?scp=85211342534&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85211342534&partnerID=8YFLogxK
U2 - 10.1016/j.bbi.2024.12.001
DO - 10.1016/j.bbi.2024.12.001
M3 - Article
C2 - 39638159
SN - 0889-1591
VL - 124
SP - 205
EP - 217
JO - Brain, Behavior, and Immunity
JF - Brain, Behavior, and Immunity
ER -