Molecular PsychiatryNeurosciencePeer-reviewed journal article
The co-chaperone Fkbp5 shapes the acute stress response in the paraventricular nucleus of the hypothalamus
Alexander S. HäusliD, Lea M. BrixiD, Jakob HartmanniD, Max L. PöhlmanniD, Juan Pablo LópeziD, Danusa MenegaziD, Elena BrivioiD, Clara EngelhardtiD, Simone RoehiD, Thomas BajajiD, Lisa Rudolph, Rainer Stoffel, Kathrin Hafner, Hannah M. GossiD, Johannes M. H. M. ReuliD, Jan M. DeussingiD, Matthias EderiD, Kerry James RessleriD, Nils C. GasseniD, Alon CheniD, Mathias V. SchmidtiD
Abstract
Disturbed activation or regulation of the stress response through the hypothalamic-pituitary-adrenal (HPA) axis is a fundamental component of multiple stress-related diseases, including psychiatric, metabolic and immune disorders. The FK506 binding protein 51 (FKBP5) is a negative regulator of the glucocorticoid receptor (GR), a main driver of HPA axis regulation, and FKBP5 polymorphisms have been repeatedly linked to stress-related disorders in humans. However, the specific role of Fkbp5 in the paraventricular nucleus of the hypothalamus (PVN) in shaping HPA axis (re)activity remains to be elucidated. Using deletion, overexpression, and rescue of Fkbp5 exclusively in the PVN, we establish the fundamental importance of Fkbp5 in the HPA axis stress response. Furthermore, we show that Fkbp5 manipulation alters GR activation and elucidate the cellular complexity in the PVN, in which Fkbp5 operates.
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