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Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis
Open accessAbstract
Stress and glucocorticoid hormones regulate hippocampal neurogenesis, but the molecular mechanisms mediating these effects are poorly understood. Here we identify the glucocorticoid receptor (GR) target gene, serum- and glucocorticoid-inducible kinase 1 (SGK1), as one such mechanism. Using a human hippocampal progenitor cell line, we found that a small molecule inhibitor for SGK1, GSK650394, counteracted the cortisol-induced reduction in neurogenesis. Moreover, gene expression and pathway analysis showed that inhibition of the neurogenic Hedgehog pathway by cortisol was SGK1-dependent. SGK1 also potentiated and maintained GR activation in the presence of cortisol, and even after cortisol withdrawal, by increasing GR phosphorylation and GR nuclear translocation. Experiments combining the inhibitor for SGK1, GSK650394, with the GR antagonist, RU486, demonstrated that SGK1 was involved in the cortisol-induced reduction in progenitor proliferation both downstream of GR, by regulating relevant target genes, and upstream of GR, by increasing GR function. Corroborating the relevance of these findings in clinical and rodent settings, we also observed a significant increase of SGK1 mRNA in peripheral blood of drug-free depressed patients, as well as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Our findings identify SGK1 as a mediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.
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“in rats exposed to unpredictable chronic mild stress and prenatal stress, as well as in patients with DD, there is a significant increase in the expression of SGK1 in the hippocampus”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Anacker et al., 2013
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“in clinical samples of DD, a significant negative correlation has been observed between the mRNA levels of SGK1 and BDNF”
From Serum/glucocorticoid regulated kinase 1 (SGK1) in neurological disorders: pain or gain (2024) · cites this paper as Anacker et al., 2013
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Metadata
- Authors
- Anacker, C., Cattaneo, A., Musaelyan, K., Zunszain, P. A., Horowitz, M., Molteni, R., Luoni, A., Calabrese, F., Tansey, K., Gennarelli, M., Thuret, S., Price, J., Uher, R., Riva, M. A., & Pariante, C. M.
- Affiliations
- National Health Service (GB)
- King's College London (GB)
- University of Milan (IT)
- Centro San Giovanni di Dio Fatebenefratelli (IT)
- Dalhousie University (CA)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2013-05-06
- Volume
- 110
- Issue
- 21
- Pages
- 8708-8713
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3666742
- OpenAlex
- W2038487059
- Cited by
- 319
- References
- 38
- Citations by year
- 2026: 12 · 2025: 16 · 2024: 21 · 2023: 23 · 2022: 33 · 2021: 34 · 2020: 29 · 2019: 25 · 2018: 20 · 2017: 28 · 2016: 28 · 2015: 20 · 2014: 22 · 2013: 6
- FWCI
- 9.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion)
- Funders
- Eli Lilly and Company
- National Alliance for Research on Schizophrenia and Depression
- Research Councils UK
- European Commission (22963, 115008)
- Canada Research Chairs
- Ministero della Salute
- Regione Lombardia
- Servier
- Medical Research Council (MR/J002739/1)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- SGK1, serum- and glucocorticoid-inducible kinase 1, glucocorticoid receptor, hippocampal neurogenesis, cortisol, depression, chronic mild stress, prenatal stress, Hedgehog signaling, glucocorticoid receptor phosphorylation, hippocampal progenitor cells, progenitor cell proliferation
- MeSH terms
- Serum-Glucocorticoid Regulated Kinases, Adult, Animals, Benzoates, Cell Line, Transformed, Cell Nucleus, Depression, Female, Glucocorticoids, Hippocampus, Humans, Hydrocortisone, Male, Middle Aged, Nerve Tissue Proteins, Receptors, Glucocorticoid, RNA, Messenger, Stress, Physiological, Signal Transduction, Mifepristone, Rats, Sprague-Dawley, Protein Serine-Threonine Kinases, Immediate-Early Proteins, Bridged Bicyclo Compounds, Heterocyclic, Active Transport, Cell Nucleus, Rats, Hedgehog Proteins, Neurogenesis
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