Serotonin mediates oestrogen stimulation of cell proliferation in the adult dentate gyrus

Characterizing the mechanisms by which endogenous factors stimulate neuroge nesis is of special interest in view of the possible implication of newly g enerated cells in hippocampal functions or disorders. The aim of this study was to determine whether serotonin (5-HT) and oestradiol (E2) act through a common pathway to increase cell proliferation in the adult dentate gyrus (DG). We also investigated the effects of long-lasting changes in oestrogen levels on cell proliferation. Combining ovariectomy with inhibition of 5-H T synthesis using p-chlorophenylalanine (PCPA) treatment produced approxima tely the same decreases in the number of bromodeoxyuridine (BrdU) and PSA-N CAM immunolabelled cells in the subgranular layer as ovariectomy alone. Adm inistration of 5-hydroxytryptophan (5-HTP) restored cell proliferation prim arily decreased by ovariectomy, whereas oestradiol was unable to reverse th is change in ovariectomized rats treated with PCPA. These findings demonstr ate that 5-HT mediates oestrogen stimulation of cell proliferation in adult dentate gyrus. However, increase in ovarian hormones during pregnancy has no effect on dentate cell proliferation. This finding suggests that concomi tant changes in other factors, such as glucocorticoids, may counterbalance the positive regulation of cell proliferation by 5-HT and oestradiol. Final ly, oestrogen may regulate structural plasticity by stimulating PSA-NCAM ex pression independently of neurogenesis, as shown for instance by the increa ses in the number of PSA-NCAM labelled cells in pregnants. As 5-HT and oest rogen are involved in mood disorders, our data suggest that the positive re gulation of cell proliferation and neuroplasticity by these two factors may contribute to restore hippocampal connectivity in depressive patients.