Mineralocorticoid receptors dampen glucocorticoid receptor sensitivity to stress via regulation of FKBP5

• Published in: Cell reports (Cambridge) Vol. 35; no. 9; p. 109185
• Main Authors: Hartmann, Jakob, Bajaj, Thomas, Klengel, Claudia, Chatzinakos, Chris, Ebert, Tim, Dedic, Nina, McCullough, Kenneth M., Lardenoije, Roy, Joëls, Marian, Meijer, Onno C., McCann, Katharine E., Dudek, Serena M., Sarabdjitsingh, R. Angela, Daskalakis, Nikolaos P., Klengel, Torsten, Gassen, Nils C., Schmidt, Mathias V., Ressler, Kerry J.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.06.2021
• Subjects: Animals; Cells, Cultured; FKBP5; Gene Deletion; Gene Expression Regulation; hippocampus; Hippocampus - metabolism; HPA axis; Humans; major depression disorder; Male; Mice; Mice, Inbred C57BL; Models, Biological; MR:GR balance; Neurons - metabolism; posttraumatic stress disorder; PTSD; Receptors, Glucocorticoid - genetics; Receptors, Glucocorticoid - metabolism; Receptors, Mineralocorticoid - genetics; Receptors, Mineralocorticoid - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; stress; Stress, Physiological; Tacrolimus Binding Proteins - genetics; Tacrolimus Binding Proteins - metabolism; PTSD; stress; hippocampus; MR:GR balance; MR; major depression disorder; HPA axis; GR; FKBP5; posttraumatic stress disorder
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109185

Responding to different dynamic levels of stress is critical for mammalian survival. Disruption of mineralocorticoid receptor (MR) and glucocorticoid receptor (GR) signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders. In this study, we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus. Biotinylated-oligonucleotide immunoprecipitation in primary hippocampal neurons reveals that MR binding, rather than GR binding, to the Fkbp5 gene regulates FKBP5 expression during baseline activity of glucocorticoids. Notably, FKBP5 and MR exhibit similar hippocampal expression patterns in mice and humans, which are distinct from that of the GR. Pharmacological inhibition and region- and cell type-specific receptor deletion in mice further demonstrate that lack of MR decreases hippocampal Fkbp5 levels and dampens the stress-induced increase in glucocorticoid levels. Overall, our findings demonstrate that MR-dependent changes in baseline Fkbp5 expression modify GR sensitivity to glucocorticoids, providing insight into mechanisms of stress homeostasis. [Display omitted] •FKBP5 and MRs, but not GRs, exhibit similar hippocampal expression patterns•MRs, rather than GRs, regulate FKBP5 expression in hippocampal neurons at baseline•Inhibition and deletion of MRs decrease hippocampal Fkbp5 mRNA levels in vivo•Forebrain MR deletion leads to GR hypersensitivity during acute stress Hartmann et al. demonstrate that MRs regulate baseline FKBP5 expression in the hippocampus. This regulation leads to a modification of GR sensitivity to glucocorticoids during acute stress. The results suggest that FKBP5 acts as a key modulator of HPA axis activity by mediating the fine-tuning of hippocampal MR:GR balance.