Center for Stress Neurobiology, Children's Hospital of Philadelphia, Abramson Research Center, 3615 Civic Center Blvd, Philadelphia, PA, 19104, USA.
Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA.
Nat Commun. 2019 Jul 17;10(1):3146. doi: 10.1038/s41467-019-10904-8.
Stress can promote the development of psychiatric disorders, though some individuals are more vulnerable to stress compared to others who are more resilient. Here we show that the sphingosine-1-phosphate receptor 3 (S1PR3) in the medial prefrontal cortex (mPFC) of rats regulates resilience to chronic social defeat stress. S1PR3 expression is elevated in the mPFC of resilient compared to vulnerable and control rats. Virally-mediated over-expression of S1PR3 in the mPFC produces a resilient phenotype whereas its knock-down produces a vulnerable phenotype, characterized by increased anxiety- and depressive-like behaviors, and these effects are mediated by TNFα. Furthermore, we show that S1PR3 mRNA in blood is reduced in veterans with PTSD compared to combat-exposed control subjects and its expression negatively correlates with symptom severity. Together, these data identify S1PR3 as a regulator of stress resilience and reveal sphingolipid receptors as important substrates of relevance to stress-related psychiatric disorders.
压力会促进精神疾病的发展，但与更有弹性的人相比，有些人更容易受到压力的影响。在这里，我们表明，大鼠内侧前额叶皮质（mPFC）中的鞘氨醇-1-磷酸受体 3（S1PR3）调节对慢性社交挫败应激的弹性。与脆弱和对照大鼠相比，弹性大鼠的 mPFC 中 S1PR3 的表达升高。在 mPFC 中过表达 S1PR3 会产生弹性表型，而敲低 S1PR3 会产生脆弱表型，其特征是焦虑和抑郁样行为增加，这些作用是由 TNFα介导的。此外，我们发现 PTSD 退伍军人的血液中的 S1PR3mRNA 减少，与战斗暴露的对照组相比，其表达与症状严重程度呈负相关。总之，这些数据表明 S1PR3 是压力弹性的调节剂，并揭示了鞘脂受体作为与应激相关的精神疾病相关的重要底物。
