title: Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor.
abstract: Antidepressants increase adult hippocampal neurogenesis in animal models, but the underlying molecular mechanisms are unknown. In this study, 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, p27(Kip1) and p57(Kip2). 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 toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans.
authors.affiliation: King's College London, Institute of Psychiatry, Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology (SPI-lab), Department of Psychological Medicine, London, UK.
authors.forename: C
authors.initials: C
authors.lastname: Anacker
authors.forename: P A
authors.initials: PA
authors.lastname: Zunszain
authors.forename: A
authors.initials: A
authors.lastname: Cattaneo
authors.forename: L A
authors.initials: LA
authors.lastname: Carvalho
authors.forename: M J
authors.initials: MJ
authors.lastname: Garabedian
authors.forename: S
authors.initials: S
authors.lastname: Thuret
authors.forename: J
authors.initials: J
authors.lastname: Price
authors.forename: C M
authors.initials: CM
authors.lastname: Pariante
mesh_terms: D000928:Antidepressive Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005786:Gene Expression Regulation / Q000187:drug effects; D006624:Hippocampus / Q000166:cytology*; D006801:Humans; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000187:drug effects*; D055495:Neurogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D011965:Receptors, Glucocorticoid / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014404:Tubulin / Q000378:metabolism
chemical_list: D000928:Antidepressive Agents; D009419:Nerve Tissue Proteins; D011965:Receptors, Glucocorticoid; C498585:TUBB3 protein, human; D014404:Tubulin; D017868:Cyclic AMP-Dependent Protein Kinases