Endogenous sphingosine 1-phosphate regulates spontaneous glutamate release from mossy fiber terminals via S1P3 receptors

Aims Previous studies have shown that sphingosine 1-phosphate (S1P) stimulates glutamate release from hippocampal neurons. The present study was designed to understand the mechanism underlying S1P-induced spontaneous glutamate release from mossy fiber terminals in the hippocampus. Main methods Slice patches were made from three different regions of neurons in rat hippocampal slices, and spontaneous α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor-mediated miniature excitatory postsynaptic currents (AMPA-mEPSCs) were monitored. Key findings Inhibitors of sphingosine kinase such as dimethylsphingosine (DMS) and 2-(p-hydroxyanilino)-4-(p-chlorophenyl) thiazole (HACPT), to suppress endogenous S1P production, significantly decreased the rate of spontaneous AMPA-mEPSCs elicited from CA3 pyramidal neurons, but not CA1 pyramidal neurons or dentate granular neurons. A similar decrease was also obtained with VPC23019, an inhibitor of S1P receptors, suramin, an inhibitor of S1P 3 receptor, U73122, an inhibitor of phospholipase C, or GF109203X, an inhibitor of protein kinase C. Significance The results of the present study show that endogenous S1P regulates spontaneous glutamate release in a restricted hippocampal area, i.e., the release from mossy fiber terminals, via S1P 3 receptors linked to G q protein. This may represent fresh insight into the regulatory mechanism of spontaneous transmitter release.