Background: An imbalance between central mineralocorticoid (MR) and glucocorticoid (GR) receptor signaling is proposed to underlie hypothalamic-pituitary-adrenal (HPA) axis dysregulation observed in stress-related psychiatric disorders; however, the underlying molecular mechanisms remain unclear. Here we show that FK506-binding protein 51 (FKBP5) plays a critical role in fine-tuning MR:GR balance in the hippocampus.
Methods: We utilized a number of analytic and causal approaches across species – biotinylated-oligonucleotide- mediated chromatin immunoprecipitation (oligoChIP) in mouse primary hippocampal neurons, single-cell RNA sequencing data, human postmortem brain tissue expression analyses, pharmacological approaches as well as region- and cell type-specific GR and MR knockout mice.
Results: OligoChIP in primary hippocampal neurons revealed that MR-, rather than GR-binding to the Fkbp5 gene regulates FKBP5 expression (one-way ANOVA: F3, 8 = 7.578, p < 0.01) during baseline activity of glucocorticoids. Notably, in mouse and human hippocampus, similar mRNA and protein expression patterns were observed for FKBP5 and MR, which were distinct from that of GR. Finally, pharmacological inhibition, region- and cell-type specific receptor deletion in mice demonstrated that lack of MR decreases hippocampal Fkbp5 levels (two-way ANOVA: genotype x hippocampal sub-region interaction F3, 88 = 77.2, p < 0.0001; n = 10 (ctrl) and n = 14 (Forebrain-specific MR knockout (MR-CKOCamk2α-Cre)) and dampens the stress-induced increase in glucocorticoid levels (two-way ANOVA: genotype x condition interaction F1, 19 = 6.228, p < 0.05).
Conclusions: Overall, our results demonstrate that MR-dependent changes in baseline Fkbp5 expression modify GR- sensitivity to glucocorticoids to ultimately alter HPA axis activity during acute stress. This provides additional insights into the molecular mechanisms underlying the MR:GR balance hypothesis. Such findings suggest that therapeutic targeting of MR, GR, and FKBP5 may be complementary in manipulating CNS and peripheral regulation of stress homeostasis.
Live Zoom Session – April 21st
Jakob Hartmann, PhD, Thomas Bajaj, Claudia Klengel, MD, Chris Chatzinakos, PhD, Nina Dedic, PhD, Kenneth M McCullough, PhD, Roy Lardenoije, PhD, Marian Joëls, PhD, Onno C Meijer, PhD, Kate E McCann, PhD, Serena M Dudek, PhD, Angela Sarabdjitsingh, PhD, Nikolaos P Daskalakis, MD, PhD, Torsten Klengel, MD, PhD, Nils C Gassen, PhD, Mathias V Schmidt, PhD, Kerry J Ressler, MD, PhD