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Antidepressants Increase Human Hippocampal Neurogenesis By Molecular Psychiatry (2011) 16, 738–750 & 2011 Macmillan Publishers Limited All rights reserved 1359-4184/11 www.nature.com/mp ORIGINAL ARTICLE Antidepressants increase human hippocampal neurogenesis by activating the glucocorticoid receptor C Anacker1,2,3, PA Zunszain1, A Cattaneo1,4, LA Carvalho1, MJ Garabedian5, S Thuret3, J Price3 and CM Pariante1,2 1King’s College London, Institute of Psychiatry, Section of Perinatal Psychiatry and Stress, Psychiatry and Immunology (SPI-lab), Department of Psychological Medicine, London, UK; 2National Institute for Health Research ‘Biomedical Research Centre for Mental Health’, Institute of Psychiatry and South London and Maudsley NHS Foundation Trust, London, UK; 3King’s College London, Institute of Psychiatry, Centre for the Cellular Basis of Behaviour (CCBB), London, UK; 4Genetics Unit, IRCCS San Giovanni di Dio, Brescia, Italy and 5Department of Microbiology, NYU School of Medicine, New York, NY, USA 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, double- cortin (Dcx)-positive neuroblasts ( þ 16%) and mature, microtubulin-associated protein-2 (MAP2)-positive neurons ( þ 26%). This effect was abolished by the GR-antagonist, RU486. Interestingly, progenitor cell proliferation, as investigated by 50-bromodeoxyuridine (BrdU) incorporation, was only increased when cells were co-treated with sertraline and the GR-agonist, dexamethasone, ( þ 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 toward an important role for the GR in the antidepressant-induced modulation of neurogenesis in humans. Molecular Psychiatry (2011) 16, 738–750; doi:10.1038/mp.2011.26; published online 12 April 2011 Keywords: adult hippocampal neurogenesis; depression; glucocorticoids; neuroplasticity; stem cells Introduction lying such effects have not been described to date. The effects of antidepressants on hippocampal neu- Several studies have shown that antidepressants rogenesis have been demonstrated for different, increase hippocampal neurogenesis in both animals chemically unrelated classes of antidepressants,1 and humans,1–5 and whether this increase in neuro- suggesting that a common molecular mechanism genesis is necessary to overcome behavioral deficits may underlie their neurogenic potential. Identifying in animal models of depression is being intensely such a mechanism would allow us to modulate debated.5–16 However, the molecular pathways under- neurogenesis, and thereby possibly counteract some of the neurobiological disturbances in depression. Notably, recent studies have suggested that gluco- Correspondence: Dr CM Pariante or Dr S Thuret, Institute of corticoids are involved in the neurogenic action Psychiatry, The James Black Centre, King’s College London, 125 of antidepressants.12,17 For example, one study has Coldharbour Lane, SE5 9NU, UK. observed that antidepressants increase hippocampal E-mails: [email protected] or [email protected] Received 18 April 2010; revised 8 February 2011; accepted 9 neurogenesis only in mice that are co-treated with 12 February 2011; published online 12 April 2011 glucocorticoid hormones, but not in control mice. Antidepressants, neurogenesis and glucocorticoid receptor C Anacker et al 739 The potential role of glucocorticoids in antidepres- fibroblast growth factor (bFGF) and 4-hydroxytamoxi- sant-induced neurogenesis is also consistent with an fen (4-OHT) for 72 h, and then washed and cultured in extensive literature, some from our own group, which media without growth factors and 4-OHT for subse- shows that antidepressants directly regulate the quent 7 days. Cells were treated with the antidepres- function of the glucocorticoid receptor (GR).18–24 The sant sertraline (1 mM), the GR-agonists, dexamethasone GR is a ligand-activated nuclear transcription factor. (1 mM) and cortisol (100 mM), the GR-antagonist RU486 Upon ligand binding, the GR translocates into the (50 nM), the PDE4-inhibitor rolipram (100 nM)orthe nucleus, binds to glucocorticoid response elements PKA-inhibitor H89 (50 nM). For these experiments, on the DNA and subsequently activates gene cells were treated during the initial proliferation phase transcription (so called transactivation). Multiple and the subsequent differentiation phase (total treat- kinases have been reported to differentially phos- ment of 10 days), or only during the proliferation phase phorylate the GR at its serine residues, S203, S211 (72 h), or only during the differentiation phase (7 days). and S226, an effect which regulates GR nuclear At the end of the total incubation time (10 days), cells translocation and GR-dependent gene transcrip- were fixed with 4% paraformaldehyde (PFA) for tion.25–29 Studies by us and others have shown that 20 min at room temperature. antidepressants also induce GR nuclear translocation and transactivation, which is, at least in part, Proliferation assay mediated by the cyclic AMP (cAMP)/protein kinase To assess progenitor cell proliferation, HPC03A/07 A (PKA) cascade.21–24,30–33 Moreover, the intracellular cells were plated as described above, and cultured availability of cAMP is tightly regulated by phospho- for 72 h in the presence of growth factors and 4-OHT. diesterase type 4 (PDE4); and, consistent with The synthetic nucleotide 50-bromodeoxyuridine PKA-dependent regulation of the GR, the PDE4 (BrdU, 10 mM) was added to the culture media 4 h inhibitor, rolipram, enhances GR activation by anti- before the end of the incubation, and cells were fixed depressants.30 as described above. Considering this body of evidence, we hypothe- sized that antidepressants modulate adult hippocam- Immunocytochemistry pal neurogenesis via a GR-dependent mechanism that Neuronal differentiation was assessed by doublecor- requires PKA signaling and GR phosphorylation. tin (Dcx), microtubulin-associated protein-2 (MAP2) To test this hypothesis in a clinically relevant and neuron-specific class III -tubulin (TuJ1) model, we have used hippocampal progenitor cells immunocytochemistry (Figure 1a, Supplementary from humans. Using this in vitro model, we have been Figure 2a). Specificity of the MAP2 antibody able to separate the direct effects of antidepressants for mature neurons in our culture was confirmed on progenitor cells from any potential indirect by co-labeling experiments and Western Blotting effects, which would be present in an in vivo model. (Supplementary Figure 11). Briefly, PFA-fixed cells Moreover, we have examined the differential effects were incubated in blocking solution (5% normal goat of antidepressants (and glucocorticoid hormones) serum, Alpha Diagnostics, San Antonio, TX, USA) in on progenitor cell proliferation and differentiation, phosphate-buffered saline containing 0.3% Triton-X as well as on GR phosphorylation, transactivation for 2 h at room temperature, and with primary and subsequent changes in gene expression. In all antibodies (rabbit anti-Dcx, 1:1000; mouse anti- our experiments, we have used the selective serotonin MAP-2 (HM), 1:500, Abcam, Cambridge, UK; rabbit reuptake inhibitor, sertraline, which has recently anti-TuJ1, 1:500, Sigma, St-Louis, MO, USA) at 4 1C been described as one of the most clinically effective over night. Cells were incubated sequentially in antidepressants.34 Confirmatory replication experi- blocking solution for 30 min, secondary antibodies ments have been conducted also using the tricyclic (Alexa 594 goat anti-rabbit, 1:1000 and Alexa 488 goat antidepressants, amitriptyline and clomipramine. anti-mouse, 1:500, Invitrogen, Paisley, UK) for 1 h and Hoechst 3 3342 dye (0.01 mg mlÀ1, Invitrogen) for 5 min at room temperature. The number of Dcx, Materials and methods MAP2 and TuJ1 positive cells over total Hoechst Cell culture 33 342 positive cells was counted in an unbiased The multipotent, human hippocampal progenitor cell setup with an inverted microscope (IX70, Olympus, line HPC03A/07 (provided by ReNeuron, Surrey, UK) Hamburg, Germany) and ImageJ 1.41 software (http:// was used for all experiments. Further information on rsbweb.nih.gov). To assess progenitor cell prolifera- this cell line and media components are available in tion, BrdU-containing cells were incubated with the Supplementary Materials. hydrochloric acid (HCl, 2 N) for 15 min at room temperature, blocking solution for 60 min
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