Decreased Sphingosine 1-Phosphate Levels in the Prefrontal Cortex of Mice Susceptible to Repeated Social Defeat Stress.

Repeated psychological stress is a major risk factor for psychiatric disorders. Sphingosine 1-phosphate (S1P), a bioactive sphingolipid, is known to contribute to regulating central nervous system functions. However, the relationship between the onset of psychological stress-induced behavioral disorders and S1P metabolism in the brain remains poorly understood. Because prefrontal cortex (PFC) and hippocampus are key brain regions involved in psychological stress responses, we investigated whether repeated social defeat stress (SDS) alters S1P metabolism in these regions. The S1P levels in the PFC, but not in the hippocampus, of mice susceptible to 4-day SDS were markedly lower than those in the control mice and were positively correlated with sociability. Additionally, mRNA expressions of an S1P-degrading enzyme Plpp3 and an inflammatory mediator Hmgb1 were increased in the PFC of 4-day SDS-susceptible mice. These results suggest that impaired S1P signaling in the PFC is associated with the onset of psychosocial stress-induced social avoidance.