Sphingosine-1-phosphate (S1P) is a lipid mediator that exerts multiple cellular functions through activation of G-proteincoupled receptors. Although the role of S1P on angiogenesis is well established, its role in neurogenesis is unknown. We examined the effects of S1P on G-protein activation in brain sections of rat embryo and on neural progenitor cells in culture. Intense S1P-stimulated [35 S]GTPcS labeling was observed as early as E15 in the neuroepithelium and differentiating fields throughout the brain, suggesting that functional S1P receptors are expressed in brain areas with active neurogenesis. mRNA transcripts for several S1P receptor subtypes (S1P 1 , S1P 2 , S1P 3 and S1P 5 ) were expressed in neural progenitor cells prepared from embryonic rat hippocampus. S1P induced phosphorylation of extracellular signal-regulated kinase (ERK) and proliferation of neural progenitor cells as determined by BrdU incorporation in a pertussis toxin-sensitive manner. These effects were prevented by the ERK signaling inhibitor U0126. S1P augmented telomerase activity in neural progenitor cells with similar potency as that of FGF-2. Furthermore, S1P induced cell-cell aggregation. This morphological change was transient and prevented by Y-27632, an inhibitor of Rhoassociated kinase. These results suggest that S1P plays a pleiotropic role in neurogenesis via pathways involving S1P receptors, MAP kinases and Rho kinase.

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Activation of the MBR in the hippocampus leads to the synthesis of allopregnanolone, an anxiolytic neurosteroid that potentiates GABA(A) receptor function.

1 Selective Serotonin Reuptake Inhibitors (SSRIs) are thought to have a delay in therapeutic e cacy because of the need to overcome the inhibitory in¯uence of raphe 5-HT 1A autoreceptors. Prolonged SSRI administration has been reported to desensitize these autoreceptors. We have used [ 35 S]-GTPgS autoradiography to determine whether this desensitization occurs at the level of receptor/G protein coupling. 2 Male mice were injected intraperitoneally once a day with saline or 20 mg kg 71¯u oxetine for either 2 days or 14 days. 5-HT 1A receptor binding and coupling to G proteins were assessed using 6 These results suggest that the desensitization of presynaptic 5-HT 1A receptor function occurs at the level of receptor-G protein interaction on dorsal raphe neurons, and may underlie the therapeutic e cacy of long-term SSRI treatment.

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