The involvement of FK506-binding protein 51 (FKBP5) in the behavioral and neuroendocrine effects of chronic social defeat stress
Abstract
Chronic stress is increasingly considered to be a main risk factor for the development of a variety of psychiatric diseases such as depression. This is further supported by an impaired negative feedback of the hypothalamic-pituitary-adrenal (HPA) axis, which has been observed in the majority of depressed patients. The effects of glucocorticoids, the main hormonal endpoint of the HPA axis, are mediated via the glucocorticoid receptor (GR) and the mineralocorticoid receptor. The FK506-binding protein 51 (FKBP5), a co-chaperone of the Hsp90 and component of the chaperone-receptor heterocomplex, has been shown to reduce ligand sensitivity of the GR. This study aimed to investigate the function of FKBP5 as a possible mediator of the stress response system and its potential role in the development of stress-related diseases. Therefore, we assessed whether mice lacking the gene encoding FKBP5 (51KO mice) were less vulnerable to the adverse effects of three weeks of chronic social defeat stress. Mice were subsequently analyzed with regards to physiological, neuroendocrine, behavioral and mRNA expression alterations. Our results show a less vulnerable phenotype of 51KO mice with respect to physiological and neuroendocrine parameters compared to wild-type animals. 51KO mice demonstrated lower adrenal weights and basal corticosterone levels, a diminished response to a novel acute stimulus and an enhanced recovery, as well as more active stress-coping behavior. These results suggest an enhanced negative glucocorticoid feedback within the HPA axis of 51KO mice, possibly modulated by an increased sensitivity of the GR. This article is part of a Special Issue entitled 'Anxiety and Depression'.
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FKBP51 knock-out mice are more resilient to chronic social defeat stress.
“Additionally, FKBP51 knock-out mice are also more resilient to CSDS (Hartmann et al., 2012).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Hartmann et al., 2012
Cites
Binder, E. B. (2009) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2009.05.021 · Cited by 968 · see citing works
Reduced levels of hsp90 compromise steroid receptor action in vivo
Picard, D., Khursheed, B., Garabedian, M. J., Fortin, M. G., Lindquist, S., & Yamamoto, K. R. (1990) · Nature · doi:10.1038/348166a0 · Cited by 787 · cited 1× · see citing works
“It is well established that malfunction of GRs due to low affinity ligand binding can be the consequence of mutations of the receptor itself or of limited hsp90 action (Bohen and Yamamoto, 1993; Brönnegard et al., 1996; Picard et al., 1990).”
BackgroundWochnik, G. M., Rüegg, J., Abel, G. A., Schmidt, U., Holsboer, F., & Rein, T. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m407498200 · Cited by 638 · see citing works
Self-citationA New First Step in Activation of Steroid Receptors
Davies, T. H., Ning, Y.-M., & Sánchez, E. R. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c100531200 · Cited by 427 · see citing works
The glucocorticoid responses are shaped by molecular chaperones
Grad, I., & Picard, D. (2007) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2007.05.018 · Cited by 423 · see citing works
The Hsp90‐binding peptidylprolyl isomerase FKBP52 potentiates glucocorticoid signaling in vivo
Riggs, D. L., Roberts, P. J., Chirillo, S. C., Cheung‐Flynn, J., Prapapanich, V., Ratajczak, T., Gaber, R., Picard, D., & Smith, D. F. (2003) · The EMBO Journal · doi:10.1093/emboj/cdg108 · Cited by 353 · see citing works
Self-citationRisk and resilience: genetic and environmental influences on development of the stress response
Gillespie, C. F., Phifer, J., Bradley, B., & Ressler, K. J. (2009) · Depression and Anxiety · doi:10.1002/da.20605 · Cited by 351 · see citing works
Segman, R. H., Shefi, N., Goltser-Dubner, T., Friedman, N., Kaminski, N., & Shalev, A. Y. (2005) · Molecular Psychiatry · doi:10.1038/sj.mp.4001636 · Cited by 281 · see citing works
Albeck, D. S., McKittrick, C. R., Blanchard, D. C., Blanchard, R. J., Nikulina, J., McEwen, B. S., & Sakai, R. R. (1997) · The Journal of Neuroscience · doi:10.1523/jneurosci.17-12-04895.1997 · Cited by 261 · see citing works
Cochaperone immunophilin FKBP52 is critical to uterine receptivity for embryo implantation
Tranguch, S., Cheung-Flynn, J., Daikoku, T., Prapapanich, V., Cox, M. B., Xie, H., Wang, H., Das, S. K., Smith, D. F., & Dey, S. K. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0505775102 · Cited by 232 · see citing works
Self-citationTatro, E. T., Everall, I. P., Kaul, M., & Achim, C. L. (2009) · Brain Research · doi:10.1016/j.brainres.2009.06.036 · Cited by 125 · see citing works
Westberry, J. M., Sadosky, P. W., Hubler, T. R., Gross, K. L., & Scammell, J. G. (2006) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2006.03.004 · Cited by 91 · see citing works
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Gene–Stress–Epigenetic regulation of FKBP5: clinical and translational implications
Zannas, A. S., Wiechmann, T., Gassen, N. C., & Binder, E. B. (2016) · Neuropsychopharmacology · doi:10.1038/npp.2015.235 · Cited by 622 · see citing works
Cortisol and major depressive disorder-translating findings from humans to animal models and Back
Nandam, L. S., Brazel, M., Zhou, M., & Jhaveri, D. J. (2020) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00974 · Cited by 265 · see citing works
Selective inhibitors of the FK506-binding protein 51 by induced fit
Gaali, S., Kirschner, A., Cuboni, S., Hartmann, J., Kozany, C., Balsevich, G., Namendorf, C., Fernandez-Vizarra, P., Sippel, C., Zannas, A. S., et al. (2015) · Nature Chemical Biology · doi:10.1038/nchembio.1699 · Cited by 245 · see citing works
Self-citationMatosin, N., Halldorsdottir, T., & Binder, E. B. (2018) · Biological Psychiatry · doi:10.1016/j.biopsych.2018.01.021 · Cited by 226 · see citing works
FKBP Ligands—Where We Are and Where to Go?
Kolos, J. M., Voll, A. M., Bauder, M., & Hausch, F. (2018) · Frontiers in Pharmacology · doi:10.3389/fphar.2018.01425 · Cited by 158 · see citing works
Self-citationMenke, A., Klengel, T., Rubel, J., Brückl, T., Pfister, H., Lucae, S., Uhr, M., Holsboer, F., & Binder, E. B. (2013) · Genes, Brain and Behavior · doi:10.1111/gbb.12026 · Cited by 151 · see citing works
Self-citationStress-responsive FKBP51 regulates AKT2-AS160 signaling and metabolic function
Balsevich, G., Häusl, A. S., Meyer, C. W., Karamihalev, S., Feng, X., Pöhlmann, M. L., Dournes, C., Uribe-Marino, A., Santarelli, S., Labermaier, C., et al. (2017) · Nature Communications · doi:10.1038/s41467-017-01783-y · Cited by 134 · see citing works
Self-citationHähle, A., Merz, S., Meyners, C., & Hausch, F. (2019) · Biomolecules · doi:10.3390/biom9010035 · Cited by 119 · see citing works
Self-citationEpigenetic mechanisms underlying learning and the inheritance of learned behaviors
Dias, B. G., Maddox, S. A., Klengel, T., & Ressler, K. J. (2015) · Trends in Neurosciences · doi:10.1016/j.tins.2014.12.003 · Cited by 125 · see citing works
Hartmann, J., Bajaj, T., Klengel, C., Chatzinakos, C., Ebert, T., Dedic, N., McCullough, K. M., Lardenoije, R., Joëls, M., Meijer, O. C., et al. (2021) · Cell Reports · doi:10.1016/j.celrep.2021.109185 · Cited by 119 · see citing works
Self-citationThe prospect of FKBP51 as a drug target
Schmidt, M. V., Paez‐Pereda, M., Holsboer, F., & Hausch, F. (2012) · ChemMedChem · doi:10.1002/cmdc.201200137 · Cited by 99 · see citing works
Self-citationTrainor, B. C., Takahashi, E. Y., Campi, K. L., Florez, S. A., Greenberg, G. D., Laman-Maharg, A., Laredo, S. A., Orr, V. N., Silva, A. L., & Steinman, M. Q. (2013) · Hormones and Behavior · doi:10.1016/j.yhbeh.2013.01.011 · Cited by 86 · see citing works
Nicolaides, N. C., Charmandari, E., Chrousos, G. P., & Kino, T. (2014) · BMC Endocrine Disorders · doi:10.1186/1472-6823-14-71 · Cited by 83 · see citing works
Homer1/mGluR5 Activity Moderates Vulnerability to Chronic Social Stress
Wagner, K. V., Hartmann, J., Labermaier, C., Häusl, A. S., Zhao, G., Harbich, D., Schmid, B., Wang, X.-D., Santarelli, S., Kohl, C., et al. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2014.308 · Cited by 67 · see citing works
Self-citationEvaluation of synthetic FK506 analogues as ligands for the FK506-binding proteins 51 and 52
Gopalakrishnan, R., Kozany, C., Gaali, S., Kress, C., Hoogeland, B., Bracher, A., & Hausch, F. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201746x · Cited by 64 · see citing works
Self-citationFKBP51 inhibits GSK3β and augments the effects of distinct psychotropic medications
Gassen, N. C., Hartmann, J., Zannas, A. S., Kretzschmar, A., Zschocke, J., Maccarrone, G., Hafner, K., Zellner, A., Kollmannsberger, L. K., Wagner, K. V., et al. (2016) · Molecular Psychiatry · doi:10.1038/mp.2015.38 · Cited by 62 · see citing works
Self-citationMetzger, M. W., Walser, S. M., Dedic, N., Aprile-Garcia, F., Jakubcakova, V., Adamczyk, M., Webb, K. J., Uhr, M., Refojo, D., Schmidt, M. V., et al. (2017) · The Journal of Neuroscience · doi:10.1523/jneurosci.3487-16.2017 · Cited by 59 · see citing works
Self-citationExploration of pipecolate sulfonamides as binders of the FK506-binding proteins 51 and 52
Gopalakrishnan, R., Kozany, C., Wang, Y., Schneider, S., Hoogeland, B., Bracher, A., & Hausch, F. (2012) · Journal of Medicinal Chemistry · doi:10.1021/jm201747c · Cited by 52 · see citing works
Structure-Based Design of High-Affinity Macrocyclic FKBP51 Inhibitors
Bauder, M., Meyners, C., Purder, P. L., Merz, S., Sugiarto, W. O., Voll, A. M., Heymann, T., & Hausch, F. (2021) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.0c02195 · Cited by 53 · see citing works
Self-citationSabbagh, J. J., Cordova, R. A., Zheng, D., Criado-Marrero, M., Lemus, A., Li, P., Baker, J. D., Nordhues, B. A., Darling, A. L., Martinez-Licha, C., et al. (2018) · ACS Chemical Biology · doi:10.1021/acschembio.8b00454 · Cited by 48 · see citing works
Maurel, O. M., Torrisi, S. A., Barbagallo, C., Purrello, M., Salomone, S., Drago, F., Ragusa, M., & Leggio, G. M. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms22105157 · Cited by 44 · see citing works
Kumar, R., Moche, M., Winblad, B., & Pavlov, P. F. (2017) · Scientific Reports · doi:10.1038/s41598-017-14731-z · Cited by 40 · see citing works
Persaud, N. S., & Cates, H. M. (2023) · eneuro · doi:10.1523/eneuro.0109-21.2021 · Cited by 41 · see citing works
“Though the researchers investigated genes under the regulation of HDAC5 in cocainetreated mice, they did not do so in CSDS mice (Renthal et al., 2007).”
BackgroundInfluentialvan Doeselaar, L., Stark, T., Mitra, S., Yang, H., Bordes, J., Stolwijk, L., Engelhardt, C., Kovarova, V., Narayan, S., Brix, L. M., et al. (2023) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2300722120 · Cited by 30 · see citing works
Self-citationAnderzhanova, E., Hafner, K., Genewsky, A. J., Soliman, A., Pöhlmann, M. L., Schmidt, M. V., Blum, R., Wotjak, C. T., & Gassen, N. C. (2020) · Neurobiology of Stress · doi:10.1016/j.ynstr.2020.100239 · Cited by 29 · see citing works
Self-citationCruz, B., Vozella, V., Carper, B. A., Xu, J. C., Kirson, D., Hirsch, S., Nolen, T., Bradley, L., Fain, K., Crawford, M., et al. (2023) · Neuropsychopharmacology · doi:10.1038/s41386-022-01497-w · Cited by 25 · see citing works
Childhood Trauma and Suicide: The Mediating Effect of Stress and Sleep
Wu, R., Zhu, H., Wu, M.-Y., Wang, G.-H., & Jiang, C.-L. (2022) · International Journal of Environmental Research and Public Health · doi:10.3390/ijerph19148493 · Cited by 20 · see citing works
Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity
Budziñski, M. L., Sokn, C., Gobbini, R., Ugo, B., Antunica-Noguerol, M., Senin, S., Bajaj, T., Gassen, N. C., Rein, T., Schmidt, M. V., et al. (2022) · Molecular Psychiatry · doi:10.1038/s41380-022-01491-0 · Cited by 17 · see citing works
Self-citationSeo, J. H., Kim, S. T., Jeon, S., Kang, J. I., & Kim, S. J. (2023) · Psychoneuroendocrinology · doi:10.1016/j.psyneuen.2023.106404 · Cited by 11 · see citing works
- Authors
- Hartmann, J., Wagner, K. V., Liebl, C., Scharf, S. H., Wang, X.-D., Wolf, M., Hausch, F., Rein, T., Schmidt, U., Touma, C., Cheung-Flynn, J., Cox, M. B., Smith, D. F., Holsboer, F., Müller, M. B., & Schmidt, M. V.
- Affiliations
- Max Planck Society (DE)
- Max Planck Institute of Psychiatry (DE)
- The University of Texas at El Paso (US)
- Mayo Clinic in Arizona (US)
- Corresponding author
- Hartmann, Jakob
- ORCID
- Venue
- Neuropharmacology
- Publisher
- Elsevier BV
- Published
- 2012-01
- Volume
- 62
- Issue
- 1
- Pages
- 332-339
- ISSN
- 0028-3908 (ISSN-L)
- OpenAlex
- W2074871646
- Cited by
- 224
- References
- 12
- Citations by year
- 2026: 10 · 2025: 10 · 2024: 9 · 2023: 17 · 2022: 15 · 2021: 20 · 2020: 17 · 2019: 17 · 2018: 13 · 2017: 13 · 2016: 20 · 2015: 15 · 2014: 20 · 2013: 10 · 2012: 15
- FWCI
- 6.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neuropharmacology (publishedVersion)
- PubMed (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- FKBP5, chronic social defeat stress, glucocorticoid receptor, hypothalamic-pituitary-adrenal axis, glucocorticoid negative feedback, depression, stress coping behavior, corticosterone, adrenal weight, Hsp90 chaperone, stress vulnerability
- MeSH terms
- Analysis of Variance, Animals, Corticosterone, Disease Models, Animal, Exploratory Behavior, Gene Expression Regulation, Locomotion, Male, Neurosecretory Systems, Receptors, Glucocorticoid, Stress, Psychological, Swimming, Receptors, Mineralocorticoid, Mice, Knockout, Maze Learning, HSP90 Heat-Shock Proteins, Tacrolimus Binding Proteins, Mice
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