Role for the kinase SGK1 in stress, depression, and glucocorticoid effects on hippocampal neurogenesis

Christoph Anacker, Annamaria Cattaneo, Ksenia Musaelyan, Patricia A. Zunszain, Mark Horowitz, Raffaella Molteni, Alessia Luoni, Francesca Calabrese, Katherine Tansey, Massimo Gennarelli, Sandrine Thuret, Jack Price, Rudolf Uher, Marco A. Riva, Carmine M. Pariante

Research output: Contribution to journalArticlepeer-review


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. Usinga humanhippocampal 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 andmaintainedGRactivation inthepresenceof 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, aswell as in the hippocampus of rats subjected to either unpredictable chronic mild stress or prenatal stress. Ourfindings identify SGK1 as amediator for the effects of cortisol on neurogenesis and GR function, with particular relevance to stress and depression.

Original languageEnglish
Pages (from-to)8708-8713
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number21
Publication statusPublished - May 21 2013


  • Antidepressants
  • Hypothalamus-pituitary-adrenal axis
  • Neuroplasticity
  • Stem cells

ASJC Scopus subject areas

  • General


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