title: FK506 binding protein 5 shapes stress responsiveness: modulation of neuroendocrine reactivity and coping behavior.
abstract: BACKGROUND
  The Hsp90 cochaperone FK506 binding protein 5 (FKBP5) is an established regulator of the glucocorticoid receptor (GR), and numerous genetic studies have linked it to stress-related diseases such as major depression or posttraumatic stress disorder. However, translational studies including genetic animal models are lacking.
  
  
  METHODS
  Mice deficient of FKBP5 were generated and analyzed in comparison with wildtype littermates. They were subjected to several test paradigms characterizing their emotionality, stress reactivity, and coping behavior as well as hypothalamus-pituitary-adrenal axis function and regulation. Moreover, protein expression of GR and FKBP5 was determined in different brain structures 8 days after stress exposure. The combined dexamethasone/corticotropin-releasing hormone test was performed both in mice and healthy human subjects of different FKBP5 genotypes. The GR function was evaluated by reporter gene assays.
  
  
  RESULTS
  Under basal conditions, deletion of FKBP5 did not change exploratory drive, locomotor activity, anxiety-related behavior, stress-coping, or depression-like behavior. After exposure to different acute stressors of sufficient intensity, however, it led to a more active coping behavior. Moreover, loss of FKBP5 decreased hypothalamus-pituitary-adrenal axis reactivity and GR expression changes in response to stressors. In mice and humans, the FKBP5 genotype also determined the outcome of the dexamethasone/corticotropin-releasing hormone test.
  
  
  CONCLUSIONS
  This study in mice and humans presents FKBP5 as a decisive factor for the physiological stress response, shaping neuroendocrine reactivity as well as coping behavior. This lends strong support to the concept emerging from human studies of FKBP5 as important factor governing gene-environment interactions relevant for the etiology of affective disorders.
authors: Research Group of Psychoneuroendocrinology, Max Planck Institute of Psychiatry, Munich, Germany.
authors: Chadi
authors: C
authors: Touma
authors: Nils Christian
authors: NC
authors: Gassen
authors: Leonie
authors: L
authors: Herrmann
authors: Joyce
authors: J
authors: Cheung-Flynn
authors: Dominik R
authors: DR
authors: Büll
authors: Irina A
authors: IA
authors: Ionescu
authors: Jan-Michael
authors: JM
authors: Heinzmann
authors: Alana
authors: A
authors: Knapman
authors: Anna
authors: A
authors: Siebertz
authors: Anna-Mareike
authors: AM
authors: Depping
authors: Jakob
authors: J
authors: Hartmann
authors: Felix
authors: F
authors: Hausch
authors: Mathias V
authors: MV
authors: Schmidt
authors: Florian
authors: F
authors: Holsboer
authors: Marcus
authors: M
authors: Ising
authors: Marc B
authors: MB
authors: Cox
authors: Ulrike
authors: U
authors: Schmidt
authors: Theo
authors: T
authors: Rein
mesh_terms: D000223:Adaptation, Psychological / Q000502:physiology*; D000328:Adult; D000818:Animals; D002478:Cells, Cultured; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003907:Dexamethasone / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004622:Embryo, Mammalian; D004644:Emotions / Q000502:physiology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005938:Glucocorticoids / Q000378:metabolism; D006801:Humans; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects / Q000235:genetics; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D018709:Statistics, Nonparametric; D013315:Stress, Psychological / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D022021:Tacrolimus Binding Proteins / Q000172:deficiency / Q000378:metabolism*; D013997:Time Factors; D055815:Young Adult; D000099159:Tacrolimus Binding Protein 5
chemical_list: D003346:Corticotropin-Releasing Hormone; D003907:Dexamethasone; D005938:Glucocorticoids; D022021:Tacrolimus Binding Proteins; D000099159:Tacrolimus Binding Protein 5