Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Carmine Pariante (1) , Christoph Anacker (1) , Patricia A Zunszain (1) , Annamaria Cattaneo (1) , Livia A Carvalho (1) , Sandrine Thuret (1) , Jack Price (1) , Michael J Garabedian (1)

1 Division of Psychological Medicine, PO51

Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. Here we used human hippocampal progenitor cells to investigate the molecular pathways involved in the antidepressant-induced modulation of neurogenesis. Because our previous studies have shown that antidepressants regulate glucocorticoid receptor (GR) function, we specifically tested whether the GR may be involved in the effects of these drugs on neurogenesis. We found that treatment (for 3-10 days) with the antidepressant, sertraline, increased neuronal differentiation via a GR-dependent mechanism. Specifically, sertraline increased both immature, doublecortin (Dcx)-positive neuroblasts (+16%), and mature, microtubulin-associated protein-2 (MAP2)-positive neurons (+26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 5'-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, (+14%) an effect which was also abolished by RU486. Furthermore, the phosphodiesterase type 4 (PDE4)-inhibitor, rolipram, enhanced the effects of sertraline, whereas the protein kinase A (PKA)-inhibitor, H89, suppressed the effects of sertraline. Indeed, sertraline increased GR transactivation, modified GR phosphorylation, and increased expression of the GR-regulated cyclin-dependent kinase-2 (CDK2) inhibitors, p27Kip1 and p57Kip2. In conclusion, our data suggest that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires PKA-signaling, GR phosphorylation, and activation of a specific set of genes. Our data point towards an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.

Mots clés: adult hippocampal neurogenesis; depression; glucocorticoids; neuroplasticity; stem cells

Carmine Pariante, Christoph Anacker, Patricia A Zunszain, Annamaria Cattaneo, Livia A Carvalho, et al.. Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor. Molecular Psychiatry, 2011, ⟨10.1038/mp.2011.26⟩. ⟨hal-00631253⟩