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Role for the Kinase SGK1 in Stress, Depression, and Glucocorticoid Effects on Hippocampal Neurogenesis

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Role for the Kinase SGK1 in Stress, Depression, and Glucocorticoid Effects on Hippocampal Neurogenesis Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis Christoph Anackera,b,c,1, Annamaria Cattaneoa,d, Ksenia Musaelyana, Patricia A. Zunszaina, Mark Horowitza, Raffaella Moltenie, Alessia Luonie, Francesca Calabresee, Katherine Tanseyf, Massimo Gennarellid,g, Sandrine Thuretc, Jack Pricec, Rudolf Uherf,h, Marco A. Rivae, and Carmine M. Pariantea,b aStress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King’s College London, London SE5 9NU, United Kingdom; bBiomedical Research Centre for Mental Health, South London and Maudsley National Health Service Foundation Trust, National Institute for Health Research, London BR3 3BX, United Kingdom; cCentre for the Cellular Basis of Behaviour, Institute of Psychiatry, King’s College London, London SE5 9NU, United Kingdom; dGenetic and Biology Section, Department of Biomedical Sciences and Biotechnology, University of Brescia, 25123 Brescia, Italy; eDepartment of Pharmacological and Biomolecular Sciences, University of Milan, 20133 Milan, Italy; fMedical Research Council Social, Genetic & Developmental Psychiatry Centre, Institute of Psychiatry, King’s College London, London SE5 8AF, United Kingdom; gGenetic Unit, Istituto di Ricovero e Cura a Carattere Scientifico San Giovanni di Dio, Fatebenefratelli Centre, 25100 Brescia, Italy; and hDepartment of Psychiatry, Dalhousie University, Halifax, Nova Scotia, Canada B3H 2E2 Edited by Bruce S. McEwen, The Rockefeller University, New York, NY, and approved April 8, 2013 (received for review January 17, 2013) Stress and glucocorticoid hormones regulate hippocampal neuro- nonmutually exclusive possibility is that SGK1 also directly en- genesis, but the molecular mechanisms mediating these effects are hances GR function and potentiates glucocorticoid effects. Here poorly understood. Here we identify the glucocorticoid receptor (GR) we examined both these possibilities. target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as We have previously used a human hippocampal progenitor cell one such mechanism. Using a human hippocampal progenitor cell line, line to examine the effects of glucocorticoids and antidepressants we found that a small molecule inhibitor for SGK1, GSK650394, on neurogenesis (3, 6, 12), and we have shown that inhibition of counteracted the cortisol-induced reduction in neurogenesis. More- Hedgehog signaling critically contributes to the reduction in neuronal over, gene expression and pathway analysis showed that inhibition of differentiation upon treatment with the human glucocorticoid hor- mone, cortisol (6). Here we investigate the role of SGK1 in these the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. effects of cortisol in vitro. Moreover, we analyze SGK1 gene ex- SGK1 also potentiated and maintainedGRactivationinthepresenceof pression in the peripheral blood of drug-free depressed patients, and cortisol, and even after cortisol withdrawal, by increasing GR phos- in the hippocampus of rats exposed to unpredictable chronic mild phorylation and GR nuclear translocation. Experiments combining stress (UCMS) or prenatal stress (PNS), two in vivo stress models the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, known to precipitate depressive behavior and to decrease hippo- demonstrated that SGK1 was involved in the cortisol-induced re- campal neurogenesis (13–15). Our findings identify SGK1 as a key duction in progenitor proliferation both downstream of GR, by enzyme involved in the downstream mechanisms by which gluco- regulating relevant target genes, and upstream of GR, by increasing corticoids reduce neurogenesis and in the upstream potentiation and GR function. Corroborating the relevance of these findings in clinical maintenance of GR function, even after glucocorticoid withdrawal. and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as Results in the hippocampus of rats subjected to either unpredictable chronic SGK1 Mediates the Cortisol-Induced Decrease in Neurogenesis. We mild stress or prenatal stress. Our findings identify SGK1 as a mediator have previously reported that GR activation increases SGK1 ex- for the effects of cortisol on neurogenesis and GR function, with par- pression, and that GR-mediated concentrations of cortisol (CORT) ticular relevance to stress and depression. decrease proliferation and neuronal differentiation of human hip- pocampal progenitor cells (3, 6). In particular, we have shown that antidepressants | hypothalamus–pituitary–adrenal axis | stem cells | the concentration of 100 μM CORT exerts consistent GR-medi- neuroplasticity ated effects on cell proliferation and neuronal differentiation, and induces GR transactivation without saturating the receptor re- sponse (6). This concentration was thus used for the present study. lucocorticoid hormones are consistently increased in severely Here we used the small molecule inhibitor for SGK1, GSK650394 Gdepressed patients and in rodent stress models (1). A large (16), to test whether SGK1 is mechanistically involved in the effects body of evidence has demonstrated that chronically high con- of CORT on neurogenesis. As hypothesized, GSK650394 (at 10 nM, centrations of glucocorticoids impair hippocampal neurogenesis, 50 nM, and 100 nM) dose-dependently counteracted the CORT- that is, the development of new neurons from stem cells in the – induced reduction in BrdU-positive, proliferating progenitor dentate gyrus, by activating the glucocorticoid receptor (GR) (1 cells (one-way ANOVA, P = 0.01, F = 4.17; Fig. 1 A and B). 6). However, the mechanisms by which GR activation reduces 1,4 neurogenesis are not fully understood. Here we explore the role of the GR target gene, serum- and glucocorticoid-regulated ki- nase 1 (SGK1), in these effects. Author contributions: C.A., S.T., J.P., R.U., M.A.R., and C.M.P. designed research; C.A., A.C., K.M., P.A.Z., M.H., R.M., A.L., and F.C. performed research; M.G. contributed new re- SGK1 is a serine/threonine kinase implicated in the cellular agents/analytic tools; C.A., A.C., P.A.Z., and K.T. analyzed data; and C.A. and C.M.P. wrote stress response and neuronal function (7). We and others have the paper. previously shown that glucocorticoids increase SGK1 expression Conflict of interest statement: J.P. acted as a consultant and received payment from in human neural stem cells and in rodent neurons (3, 8). Impor- ReNeuron Group within the last 2 y. C.M.P. has received fees as a speaker or as a mem- tantly, SGK1 mediates some glucocorticoid effects on brain func- ber of advisory board, as well as research funding, from pharmaceutical companies tion; for example, acute stress enhances neuronal excitability and that commercialize or are developing antidepressants in the last 3 y, such as Lilly, working memory in the rodent prefrontal cortex via glucocorticoid- Servier, and Janssen. M.A.R. has received compensation as speaker/consultant for As- induced activation of SGK1 (9), and chronic stress causes mor- traZeneca, Bristol-Myers Squibb, Eli Lilly, Servier, and Takeda. P.A.Z. has received phological oligodendrocyte abnormalities by up-regulating SGK1 speaker fees from Servier. in the murine corpus callosum (10). These data suggest that SGK1 This article is a PNAS Direct Submission. may be a downstream mediator of glucocorticoid effects on the Freely available online through the PNAS open access option. brain. However, recent evidence has also suggested that enhanced 1To whom correspondence should be addressed. E-mail: [email protected]. SGK1 expression is associated with greater GR-mediated gene This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. expression in response to glucocorticoids (11). Therefore, another, 1073/pnas.1300886110/-/DCSupplemental. 8708–8713 | PNAS | May 21, 2013 | vol. 110 | no. 21 www.pnas.org/cgi/doi/10.1073/pnas.1300886110 Downloaded by guest on September 29, 2021 GSK650394 alone did not exert any effects on proliferation at (Fig. 1D). In line with our findings on proliferation, the dose of these concentrations (one-way ANOVA, P = 0.84, F1,3 = 0.178; GSK650394 that most effectively counteracted the effects of CORT Fig. 1C), indicating that SGK1 indeed mediates the effect of on proliferation (100 nM, as shown in Fig. 1B) also counteracted CORT, but does not eliciting any effect by itself. the CORT-induced reduction in Dcx-positive (P = 0.003; Fig. 1E) We also examined differentiation into Dcx-positive neuroblasts and in MAP2-positive cells (P = 0.03; Fig. 1F). Taken together, and into microtubule-associated protein 2 (MAP2)-positive neurons these data demonstrate that CORT decreases hippocampal progenitor cell proliferation and neuronal differentiation via an SGK1-dependent mechanism. A CORT (100 µM) + Cortisol Increases SGK1 Expression. We then further characterized veh CORT (100 µM) GSK650394 (100nM) the time course of CORT-induced SGK1 expression. SGK1 mRNA was marginally elevated after 1 h (1.3 ± 0.2 fold, P = 0.11), but significantly increased after 3 h (1.7 ± 0.08 fold, P = 0.01), 12 h (1.7 ± 0.03, P = 0.002) and 72 h (1.7 ± 0.09 fold, P = 0.02) of treatment (Fig. 2A). Moreover, the GR-antagonist, RU486 (50 nM), abolished the CORT-induced increase in SGK1 mRNA BrdU / Hoechst BrdU / Hoechst BrdU / Hoechst (Fig. S1A), confirming that this effect is GR-dependent. In line with our findings on the mRNA level, no changes in SGK1 protein
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