Analysis of the cerebellar molecular stress response led to first evidence of a role for FKBP51 in brain FKBP52 expression in mice and humans

L. Herrmann, T. Ebert, H. Rosen, B. Novak, A. Philipsen, C. Touma, M. Schreckenbach, N.C. Gassen, T. Rein, U. Schmidt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

3 Citations (Web of Science)

Abstract

As the cerebellar molecular stress response is understudied, we assessed protein expression levels of hypothalamic-pituitary-adrenal (HPA) axis regulators and neurostructural markers in the cerebellum of a male PTSD mouse model and of unstressed vs. stressed male FK506 binding protein 51 (Fkbp5) knockout (KO) vs. wildtype mice. We explored the translatability of our findings in the Fkbp5 KO model to the situation in humans by correlating mRNA levels of candidates with those of FKBP5 in two whole transcriptome datasets of postmortem human cerebellum and in blood of unstressed and stressed humans. Fkbp5 deletion rescued the stressinduced loss in hippocampal, prefrontal cortical, and, possibly, also cerebellar FKBP52 expression and modulated post-stress cerebellar expression levels of the glucocorticoid receptor (GR) and possibly (trend) also of glial fibrillary acidic protein (GFAP). Accordingly, expression levels of genes encoding for these three genes correlated with those of FKBP5 in human post-mortem cerebellum, while other neurostructural markers were not related to Fkbp5 either in mouse or human cerebellum. Also, gene expression levels of the two immunophilins correlated inversely in the blood of unstressed and stressed humans. We found transient changes in FKBP52 and persistent changes in GR and GFAP in the cerebellum of PTSD-like mice. Altogether, upon elucidating the cerebellar stress response we found first evidence for a novel facet of HPA axis regulation, i.e., the ability of FKBP51 to modulate the expression of its antagonist FKBP52 in the mouse and, speculatively, also in the human brain and blood and, moreover, detected long-term single stress-induced changes in expression of cerebellar HPA axis regulators and neurostructural markers of which some might contribute to the role of the cerebellum in fear extinction.
Original languageEnglish
Article number100401
Number of pages11
JournalNeurobiology of Stress
Volume15
DOIs
Publication statusPublished - 1 Nov 2021

Keywords

  • FKBP5 knockout
  • PTSD mouse model
  • HPA axis
  • FKBP52
  • Cerebellum
  • GLUCOCORTICOID-RECEPTOR
  • GENE-EXPRESSION
  • HIPPOCAMPUS
  • MODULATION
  • MODEL
  • REACTIVITY
  • DISORDERS

Cite this