title: Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis.
abstract: 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.
authors: Stress, Psychiatry and Immunology Laboratory, Department of Psychological Medicine, Institute of Psychiatry, King's College London, London SE5 9NU, United Kingdom. Christoph.Anacker@kcl.ac.uk
authors: Christoph
authors: C
authors: Anacker
authors: Annamaria
authors: A
authors: Cattaneo
authors: Ksenia
authors: K
authors: Musaelyan
authors: Patricia A
authors: PA
authors: Zunszain
authors: Mark
authors: M
authors: Horowitz
authors: Raffaella
authors: R
authors: Molteni
authors: Alessia
authors: A
authors: Luoni
authors: Francesca
authors: F
authors: Calabrese
authors: Katherine
authors: K
authors: Tansey
authors: Massimo
authors: M
authors: Gennarelli
authors: Sandrine
authors: S
authors: Thuret
authors: Jack
authors: J
authors: Price
authors: Rudolf
authors: R
authors: Uher
authors: Marco A
authors: MA
authors: Riva
authors: Carmine M
authors: CM
authors: Pariante
mesh_terms: D021581:Active Transport, Cell Nucleus / Q000187:drug effects; D000328:Adult; D000818:Animals; D001565:Benzoates / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology; D002461:Cell Line, Transformed; D002467:Cell Nucleus / Q000378:metabolism / Q000473:pathology; D003863:Depression / Q000201:enzymology* / Q000473:pathology; D005260:Female; D005938:Glucocorticoids / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006624:Hippocampus / Q000201:enzymology* / Q000473:pathology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism*; D017874:Immediate-Early Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D015735:Mifepristone / Q000494:pharmacology; D009419:Nerve Tissue Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism*; D055495:Neurogenesis; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011965:Receptors, Glucocorticoid / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological; D000099184:Serum-Glucocorticoid Regulated Kinases
chemical_list: D001565:Benzoates; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005938:Glucocorticoids; D053823:Hedgehog Proteins; D006854:Hydrocortisone; D017874:Immediate-Early Proteins; D015735:Mifepristone; D009419:Nerve Tissue Proteins; D017346:Protein Serine-Threonine Kinases; D012333:RNA, Messenger; D011965:Receptors, Glucocorticoid; D000099184:Serum-Glucocorticoid Regulated Kinases; C532254:2-cyclopentyl-4-(5-phenyl-1H-pyrrolo(2,3-b)pyridin-3-yl)-benzoic acid
keywords: antidepressants; hypothalamus–pituitary–adrenal axis; neuroplasticity; stem cells
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