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.
Key Words
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References
- Polymorphisms in FKBP5 are associated with increased recurrence of depressive episodes and rapid response to antidepressant treatment.Nat Genet. 2004; 36: 1319-1325
- Association of FKBP5 polymorphisms and childhood abuse with risk of posttraumatic stress disorder symptoms in adults.JAMA. 2008; 299: 1291-1305
- Polymorphisms in the FKBP5 gene region modulate recovery from psychosocial stress in healthy controls.Eur J Neurosci. 2008; 28: 389-398
- The FKBP5-gene in depression and treatment response—an association study in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Cohort.Biol Psychiatry. 2008; 63: 1103-1110
- Polymorphisms in FKBP5 are associated with peritraumatic dissociation in medically injured children.Mol Psychiatry. 2005; 10: 1058-1059
- Family-based association of FKBP5 in bipolar disorder.Mol Psychiatry. 2008; 14: 261-268
- Gene expression patterns associated with posttraumatic stress disorder following exposure to the World Trade Center attacks.Biol Psychiatry. 2009; 66: 708-711
- FKBP54, a novel FK506-binding protein in avian progesterone receptor complexes and HeLa extracts.J Biol Chem. 1993; 268: 24270-24273
- Glucocorticoid-resistant B-lymphoblast cell line derived from the Bolivian squirrel monkey (Saimiri boliviensis boliviensis).Lab Anim Sci. 1998; 48: 364-370
- Glucocorticoid resistance in the squirrel monkey is associated with overexpression of the immunophilin FKBP51.J Clin Endocrinol Metab. 1999; 84: 663-669
- Molecular determinants of glucocorticoid receptor function and tissue sensitivity to glucocorticoids.Endocr Rev. 1996; 17: 245-261
- Glucocorticoid hormone resistance during primate evolution: Receptor-mediated mechanisms.Proc Natl Acad Sci U S A. 1982; 79: 2036-2040
- The new world primates as animal models of glucocorticoid resistance.Adv Exp Med Biol. 1986; 196: 129-144
- Squirrel monkey immunophilin FKBP51 is a potent inhibitor of glucocorticoid receptor binding.Endocrinology. 2000; 141: 4107-4113
- The Hsp90-binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo.EMBO J. 2003; 22: 1158-1167
- FK506-binding proteins 51 and 52 differentially regulate dynein interaction and nuclear translocation of the glucocorticoid receptor in mammalian cells.J Biol Chem. 2005; 280: 4609-4616
- Overexpression of the FK506-binding immunophilin FKBP51 is the common cause of glucocorticoid resistance in three New World primates.Gen Comp Endocrinol. 2001; 124: 152-165
- Functional analysis of the Hsp90-associated human peptidyl prolyl cis/trans isomerases FKBP51, FKBP52 and Cyp40.J Mol Biol. 2001; 308: 795-806
- Differential impact of tetratricopeptide repeat proteins on the steroid hormone receptors.PLoS One. 2010; 5: e11717
- Stress and the brain: From adaptation to disease.Nat Rev Neurosci. 2005; 6: 463-475
- The role of childhood trauma in the neurobiology of mood and anxiety disorders: Preclinical and clinical studies.Biol Psychiatry. 2001; 49: 1023-1039
- Life stress, genes, and depression: Multiple pathways lead to increased risk and new opportunities for intervention.Sci STKE. 2004; 2004: re5
- The corticosteroid receptor hypothesis of depression.Neuropsychopharmacology. 2000; 23: 477-501
- Genetics of stress response and stress-related disorders.Dialogues Clin Neurosci. 2006; 8: 433-444
- Glucocorticoids.Ann N Y Acad Sci. 2009; 1179: 19-40
- Prediction of medium-term outcome by cortisol response to the combined dexamethasone-CRH test in patients with remitted depression.Am J Psychiatry. 1999; 156: 949-951
- Stress and affective disorders: Animal models elucidating the molecular basis of neuroendocrine-behavior interactions.Pharmacopsychiatry. 2011; 44: S15-S26
- Impaired type II glucocorticoid-receptor function in mice bearing antisense RNA transgene.Nature. 1992; 355: 725-728
- Increased glucocorticoid receptor gene promoter activity after antidepressant treatment.Mol Pharmacol. 1992; 41: 1016-1022
- Acquired deficit of forebrain glucocorticoid receptor produces depression-like changes in adrenal axis regulation and behavior.Proc Natl Acad Sci U S A. 2005; 102: 473-478
- Inhibition of GR-mediated transcription by p23 requires interaction with Hsp90.FEBS Lett. 2004; 560: 35-38
- Activity of the glucocorticoid receptor in G2 and mitosis.Mol Endocrinol. 2002; 16: 1352-1366
- Essential role of the unusual DNA binding motif of BAG-1 for inhibition of the glucocorticoid receptor.J Biol Chem. 2003; 278: 4926-4931
- Antidepressants differentially influence the transcriptional activity of the glucocorticoid receptor in vitro.Neuroendocrinology. 2003; 78: 12-22
- The ascent of mouse: advances in modelling human depression and anxiety.Nat Rev Drug Discov. 2005; 4: 775-790
- Increased anxiety-related behaviour in Hint1 knockout mice.Behav Brain Res. 2011; 220: 305-311
- Mice selected for high versus low stress reactivity: A new animal model for affective disorders.Psychoneuroendocrinology. 2008; 33: 839-862
- The use of behavioral test batteries, II: effect of test interval.Physiol Behav. 2006; 87: 95-102
- Hypothalamic integration of central and peripheral clocks.Nat Rev Neurosci. 2001; 2: 521-526
- Rhythmicity in mice selected for extremes in stress reactivity: Behavioural, endocrine and sleep changes resembling endophenotypes of major depression.PLoS One. 2009; 4: e4325
- Combined dexamethasone/corticotropin releasing hormone test predicts treatment response in major depression—a potential biomarker?.Biol Psychiatry. 2007; 62: 47-54
- Expression and regulation of the Fkbp5 gene in the adult mouse brain.PLoS One. 2011; 6: e16883
- Chronic corticosterone exposure increases expression and decreases deoxyribonucleic acid methylation of Fkbp5 in mice.Endocrinology. 2010; 151: 4332-4343
- The Hsp90 cochaperone, FKBP51, increases Tau stability and polymerizes microtubules.J Neurosci. 2010; 30: 591-599
- FKBP51 affects cancer cell response to chemotherapy by negatively regulating Akt.Cancer Cell. 2009; 16: 259-266
- Role of FK506-binding protein 51 in the control of apoptosis of irradiated melanoma cells.Cell Death Differ. 2010; 17: 145-157
- Characterization of a novel gain of function glucocorticoid receptor knock-in mouse.J Biol Chem. 2009; 284: 6249-6259
- A critical role of helix 3-helix 5 interaction in steroid hormone receptor function.Proc Natl Acad Sci U S A. 2005; 102: 2707-2712
- Effects of stress throughout the lifespan on the brain, behaviour and cognition.Nat Rev Neurosci. 2009; 10: 434-445
- Maternal care, hippocampal glucocorticoid receptors, and hypothalamic-pituitary-adrenal responses to stress.Science. 1997; 277: 1659-1662
- Expression of glucocorticoid receptor and early growth response gene 1 during postnatal development of two inbred strains of mice exposed to early life stress.Dev Neurosci. 2010; 32: 139-148
- Long-term adaptations in glucocorticoid receptor and mineralocorticoid receptor mRNA and negative feedback on the hypothalamo-pituitary-adrenal axis following neonatal maternal separation.Biol Psychiatry. 2004; 55: 367-375
- Prenatal glucocorticoid programming of brain corticosteroid receptors and corticotrophin-releasing hormone: Possible implications for behaviour.Neuroscience. 2001; 104: 71-79
- Epigenetic regulation of the glucocorticoid receptor in human brain associates with childhood abuse.Nat Neurosci. 2009; 12: 342-348
- Regional specificity of brain glucocorticoid receptor mRNA alterations in subjects with schizophrenia and mood disorders.Mol Psychiatry. 2002; 7 (924): 985-994
- Reversal of maternal programming of stress responses in adult offspring through methyl supplementation: Altering epigenetic marking later in life.J Neurosci. 2005; 25: 11045-11054
- Epigenetic programming by maternal behavior.Nat Neurosci. 2004; 7: 847-854
- Gender differences in depression.Int Rev Psychiatry. 2010; 22: 429-436
- Variations in FKBP5 and BDNF genes are suggestively associated with depression in a Swedish population-based cohort.J Affect Disord. 2010; 125: 249-255
- Intronic hormone response elements mediate regulation of FKBP5 by progestins and glucocorticoids.Cell Stress Chaperones. 2004; 9: 243-252
- Glucocorticoid receptor activates poised FKBP51 locus through long-distance interactions.Mol Endocrinol. 2010; 24: 511-525
- Neuropsin cleaves EphB2 in the amygdala to control anxiety.Nature. 2011; 473: 372-375
- Interaction of FKBP5 with childhood adversity on risk for post-traumatic stress disorder.Neuropsychopharmacology. 2010; 35: 1684-1692
- Interaction of FKBP5, a stress-related gene, with childhood trauma increases the risk for attempting suicide.Neuropsychopharmacology. 2010; 35: 1674-1683
Zimmermann P, Brückl T, Nocon A, Pfister H, Binder EB, Uhr M, et al. (in press): Interaction of variants in the FKBP5 gene and adverse life events in predicting the first depression onset: Results from a ten-year prospective community study. Am J Psychiatry. doi:10.1176/appi.ajp.2011.10111577.
Article info
Publication history
Published online: September 12, 2011
Accepted:
July 19,
2011
Received in revised form:
July 16,
2011
Received:
April 28,
2011
Footnotes
Authors US and TR contributed equally to this work.
Identification
Copyright
© 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
