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

Leonie Herrmann; Tim Ebert; Helena Rosen; Bozidar Novak; Alexandra Philipsen; Chadi Touma; Monika Schreckenbach; Nils C Gassen; Theo Rein; Ulrike Schmidt

doi:10.1016/j.ynstr.2021.100401

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

Neurobiol Stress. 2021 Sep 22:15:100401. doi: 10.1016/j.ynstr.2021.100401. eCollection 2021 Nov.

Authors

Leonie Herrmann^{1

2}, Tim Ebert³, Helena Rosen³, Bozidar Novak², Alexandra Philipsen³, Chadi Touma⁴, Monika Schreckenbach^{2

5}, Nils C Gassen^{2

3}, Theo Rein², Ulrike Schmidt^{2

3

6

7}

Affiliations

¹ German Center for Diabetes Research (DZD), Ingolstädter Landstr. 1, 85764, Neuherberg, Germany.
² Max Planck Institute of Psychiatry, Kraepelinstrasse 2-10, 80804, München, Germany.
³ Department of Psychiatry and Psychotherapy, University Hospital Bonn, Venusberg-Campus 1, 53127, Bonn, Germany.
⁴ Department of Behavioural Biology, University of Osnabrück, Barbarastrasse 11, 49076, Osnabrück, Germany.
⁵ Verein Zur Förderung der Klinischen Verhaltenstherapie (VFKV), Ausbildungsinstitut München gGmbH, Lindwurmstr. 117, 80337, München, Germany.
⁶ Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, University of Göttingen, Von-Siebold-Str. 5, 37075, Göttingen, Germany.
⁷ Maastricht University Medical Centre, School for Mental Health and Neuroscience, Department of Psychiatry and Neuropsychology, Universiteitssingel 50, 6229 ER, PO Box 616 6200 MD, Maastricht, the Netherlands.

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 post-mortem human cerebellum and in blood of unstressed and stressed humans. Fkbp5 deletion rescued the stress-induced 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.

Keywords: Cerebellum; FKBP5 knockout; FKBP52; HPA axis; PTSD mouse model.