Proceedings of The Physiological Society

King's College London (2011) Proc Physiol Soc 22, PC28

Poster Communications

Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor

C. Anacker1, P. A. Zunszain1, A. Cattaneo2, L. A. Carvalho1, S. Thuret1, J. Price1, C. M. Pariante1

1. Centre for the Cellular Basis of Behaviour, King's College London, Institute of Psychiatry, London, United Kingdom. 2. Genetics Unit, IRCCS San Giovanni di Dio, Brescia, Italy.

Antidepressants increase adult hippocampal neurogenesis in animal models, and indeed, this increase in neurogenesis has been shown to be required for antidepressants to alleviate depressive-like behaviour in rodents (1). However, the molecular mechanisms underlying the effects of antidepressants on neurogenesis are unknown. Studies by us and others have shown that antidepressants regulate the function of the glucocorticoid receptor (GR) in animals and in cellular models (2). Here we wanted to test specifically whether the GR may be involved in the effects of antidepressants on human neurogenesis. We therefore used a human hippocampal progenitor cell line (HPC03A/07, from ReNeuron, UK) to investigate the molecular pathways involved in the antidepressant-induced regulation of neurogenesis. We treated cells with the antidepressant, sertraline (1μM), for 10 days and investigated neuronal differentiation by doublecortin (Dcx) and by microtubulin-associated protein-2 (MAP2) immunocytochemistry. Cell proliferation was assessed by 5’-bromodeoxyuridine (BrdU, 10μM) incorporation and immunocytochemistry after 3 days of treatment. Gene expression and GR-phosphorylation upon antidepressant treatment was investigated by quantitative Real-Time PCR and by Western Blot, respectively. Our data show that sertraline increases both immature, Dcx-positive neuroblasts (by 16±2%, p<0.001, n=3), and mature, MAP2-positive neurons (by 26±4%, p<0.01, n=3). This effect was abolished by the GR-antagonist, RU486 (at 50nM). Interestingly, progenitor cell proliferation was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone (1μM) (by 14±3%, p<0.05, n=6), an effect which was also abolished by RU486. Moreover, sertraline increased GR phosphorylation at its serine residue S203 (by 1.6±0.2 fold, p<0.05, n=4), increased GR transactivation (by 20±3%, p<0.05, n=3), and increased expression of the GR-regulated cyclin dependent kinase-2 (CDK2) inhibitors, p27Kip1 (by 1.9±0.2 fold, p<0.05, n=3) and p57Kip2 (by 1.8±0.2 fold, p<0.05, n=3). In conclusion, our data demonstrate that the antidepressant, sertraline, increases human hippocampal neurogenesis via a GR-dependent mechanism that requires GR phosphorylation and activation of a specific set of genes, including p27Kip1 and p57Kip2. Our data point towards an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans and may provide a future drug target to overcome neurogenesis-related disturbances in depression.

Where applicable, experiments conform with Society ethical requirements