Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

• DOI: 10.1038/mp.2011.26
• Publication Date: 2011-04-12T08:05:05Z
• Authors: C Anacker; P A Zunszain; A Cattaneo; L A Carvalho; M J Garabedian; S Thuret; J Price; C M Pariante
• Keywords: Sertraline; Rolipram; Doublecortin

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, we used human progenitor cells to investigate pathways involved antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, specifically tested whether GR may be effects these drugs on We found treatment (for 3-10 days) with antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline both immature, doublecortin (Dcx)-positive neuroblasts (+16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by GR-antagonist, RU486. Interestingly, cell proliferation, as investigated 5'-bromodeoxyuridine (BrdU) incorporation, only when were co-treated GR-agonist, dexamethasone, (+14%) an which also Furthermore, phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced whereas protein kinase A (PKA)-inhibitor, H89, suppressed sertraline. Indeed, transactivation, modified phosphorylation expression GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27(Kip1) p57(Kip2). conclusion, data suggest increases mechanism requires PKA signaling, activation specific set genes. Our point toward important role for humans.