Journal Article

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

Zunszain, P A, Carvalho, L A, Garabedian, M J, Anacker, C, Cattaneo, A, Pariante, C M, Thuret, S, Price, J

2011

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/378/368 / 631/92/609 / Adult and adolescent clinical studies / Antidepressants / Antidepressive Agents - pharmacology / Behavioral Sciences / Biological and medical sciences / Biological Psychology / Cell Differentiation - drug effects / Cell growth / Cell Line / Cell Proliferation - drug effects / Cyclic AMP-Dependent Protein Kinases - metabolism / Cyclin-dependent kinases / Depression / Dosage and administration / Dose-Response Relationship, Drug / Experiments / Gene Expression Regulation - drug effects / Genetic aspects / Growth factors / Hippocampus - cytology / Humans / Kinases / Ligands / Medical sciences / Medicine / Medicine & Public Health / Mental depression / Mood disorders / Nerve Tissue Proteins - metabolism / Neural receptors / Neural Stem Cells - drug effects / Neurogenesis / Neurogenesis - drug effects / Neuropharmacology / Neurosciences / Original / original-article / Pharmacology. Drug treatments / Pharmacotherapy / Phosphorylation / Phosphorylation - drug effects / Physiological aspects / Proteins / Psychiatry / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer / Psychoanaleptics: cns stimulant, antidepressant agent, nootropic agent, mood stabilizer..., (alzheimer disease) / Psychology. Psychoanalysis. Psychiatry / Psychopathology. Psychiatry / Psychopharmacology / Receptors, Glucocorticoid - genetics / Receptors, Glucocorticoid - metabolism / Signal Transduction - drug effects / Time Factors / Tubulin - metabolism