Pharmacological Inhibition of the Psychiatric Risk Factor FKBP51 Has Anxiolytic Properties
Open accessAbstract
Anxiety-related psychiatric disorders represent one of the largest health burdens worldwide. Single nucleotide polymorphisms of the FK506 binding protein 51 (FKBP51) gene have been repeatedly associated with anxiety-related disorders and stress sensitivity. Given the intimate relationship of stress and anxiety, we hypothesized that amygdala FKBP51 may mediate anxiety-related behaviors. Mimicking the stress effect by specifically overexpressing FKBP51 in the basolateral amygdala (BLA) or central amygdala resulted in increased anxiety-related behavior, respectively. In contrast, application of a highly selective FKBP51 point mutant antagonist, following FKBP51(mut) BLA-overexpression, reduced the anxiogenic phenotype. We subsequently tested a novel FKBP51 antagonist, SAFit2, in wild-type mice via BLA microinjections, which reduced anxiety-related behavior. Remarkably, the same effect was observed following peripheral administration of SAFit2. To our knowledge, this is the first in vivo study using a specific FKBP51 antagonist, thereby unraveling the role of FKBP51 and its potential as a novel drug target for the improved treatment of anxiety-related disorders.
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Viral overexpression of mutant FKBP51 in the basolateral amygdala elicited anxiety-like behaviors in mice.
“In a follow-up study, researchers virally overexpressed mutant FKBP51 in the BLA, which is involved in pavlovian fear learning and receives sensory input from the parietal, cingulate, and prefrontal cortices, elicited anxiety-like behaviors in mice (Pessoa, 2010; Hartmann et al., 2015).”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Hartmann et al., 2015
Treatment with Ligand2, an antagonist specific to mutant FKBP51, had significant anxiolytic results in mice, measured by the open field, EPM, and light/dark box tests.
“Treatment with Ligand2, an antagonist specific to mutant FKBP51, had significant anxiolytic results in these mice, measured by the open field, EPM, and light/dark box tests.”
From The Epigenetics of Anxiety Pathophysiology: A DNA Methylation and Histone Modification Focused Review (2023) · cites this paper as Hartmann et al., 2015
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InfluentialSelf-citationFK506 binding protein 51 integrates pathways of adaptation
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“From earlier experiments we know that SAFit2 induces (positive) behavioral effects on anxiety-related behavior when used at higher doses or when combined with a stressful challenge (Hartmann et al., 2015).”
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“This time point was chosen based on previously published work that found SAFit2 administration produced anxiolytic effects in mice when administered 16 hours prior to testing, but had no effect when administered 1 hour prior to testing (Hartmann et al., 2015).”
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“is has anxiolytic effects and increases stress coping (Gaali et al., 2015; Hartmann et al., 2015).”
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“The important role of this interaction has been corroborated by the effects of the selective FKBP5 antagonist SAFit2 (Hartmann et al., 2015).”
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“FKBP5 inhibitors, such as SAFit2 (Hartmann et al. 2015), are being developed and could prove to be useful for facilitating exposure therapy in patients with”
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FKBP5: A Key Mediator of How Vertebrates Flexibly Cope with Adversity
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“However, no changes were seen in ventral hippocampus and a different study found that overexpression of FKBP5 in the dorsal hippocampus did not have an effect on anxiety-like behaviors [108].”
ResultCruz, 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
“SAFit2 was administered 16 h prior to each test [28], and the doses selected were 10 and 20mg/kg based on prior literature [29, 30].”
MethodKönig, L., Kalinichenko, L. S., Huber, S. E., Voll, A. M., Bauder, M., Kornhuber, J., Hausch, F., & Müller, C. P. (2019) · Addiction Biology · doi:10.1111/adb.12758 · Cited by 28 · see citing works
“The FKBP51 antagonist, SAFit2, was synthetized as described previously.(29,31) For intraperitoneal injections, SAFit2 was solubilized in vehicle consisting of 4% EtOH, 5% Tween80, and 5% PEG400 in”
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“Alternatively, the time of testing after SAFit2 administration may have been too soon, since one study found a decrease in anxiety-like behavior 16 h, but not 1 h, following SAFit2 administration (Hartmann et al., 2015).”
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“This is consistent with the finding that inhibition or deletion of the protein reduces anxiety-related behaviour in mice [25,26].”
ResultFKBP51 in the Oval Bed Nucleus of the Stria Terminalis Regulates Anxiety-Like Behavior
Engelhardt, C., Tang, F., Elkhateib, R., Bordes, J., Brix, L. M., van Doeselaar, L., Häusl, A. S., Pöhlmann, M. L., Schraut, K., Yang, H., et al. (2021) · eNeuro · doi:10.1523/eneuro.0425-21.2021 · Cited by 20 · see citing works
“…contrast to most of the findings in other brain regions, where virally-mediated Fkbp5-OE resulted in an anxiogenic phenotype (Attwood et al., 2011; Hartmann et al., 2015; Criado-Marrero et al., 2019), whereas Fkbp5-KO or pharmacological inhibition were associated with more resilient behavior…”
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Crabp1 Modulates HPA Axis Homeostasis and Anxiety-like Behaviors by Altering FKBP5 Expression
Lin, Y.-L., Wei, C.-W., Lerdall, T., Nhieu, J., & Wei, L.-N. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222212240 · Cited by 18 · see citing works
“FKBP5 is known to suppress GR signaling thereby regulating feedback inhibition in the HPA axis [9,10,21,22].”
BackgroundSequencing the serotonergic neuron translatome reveals a new role for Fkbp5 in stress
Lesiak, A. J., Coffey, K. R., Cohen, J. H., Liang, K. J., Chavkin, C., & Neumaier, J. F. (2020) · Molecular Psychiatry · doi:10.1038/s41380-020-0750-4 · Cited by 21 · see citing works
Tricyclic antidepressants target FKBP51 SUMOylation to restore glucocorticoid receptor activity
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“Viral overexpression of FKBP51 Viral overexpression was performed using an adeno-associated bicistronic AAV1/2 vector (GeneDetect) as described in [41].”
BackgroundMethodInfluentialSelf-citationCentral Neuroepigenetic Regulation of the Hypothalamic–Pituitary–Adrenal Axis
Dick, A. L. W., & Provençal, N. (2018) · Progress in molecular biology and translational science · doi:10.1016/bs.pmbts.2018.04.006 · Cited by 17 · see citing works
FKBP51 in glutamatergic forebrain neurons promotes early life stress inoculation in female mice
van Doeselaar, L., Abromeit, A., Štark, T., Menegaz, D., Ballmann, M., Mitra, S., Yang, H., Rehawi, G., Huettl, R.-E., Bordes, J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-57952-x · Cited by 14 · see citing works
Self-citationMultimodal Associations of FKBP5 Methylation with Emotion-Regulatory Brain Circuits.
Kremer, T. L., Chen, J., Buhl, A., Berhe, O., Bilek, E., Geiger-Primo, L. S., Ma, R., Moessnang, C., Reichert, M., Reinhard, I., et al. (2024) · Biological Psychiatry · doi:10.1016/j.biopsych.2024.03.003 · Cited by 15 · see citing works
“Conversely, pharmacological inhibition of FKBP5 has anxiolytic properties and facilitates stress coping (25, 27).”
Dick, A. L. W., Khermesh, K., Paul, E. D., Stamp, F., Levanon, E. Y., & Chen, A. (2019) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2019.00277 · Cited by 14 · see citing works
“One day following the final defeat, all mice were subjected to the social interaction (SI) test to enable classification of susceptible (SUS) [social interaction (SI) ratio <1] and resilient mice (RES) (SI ratio >1) as previously described (22, 24).”
MethodSelf-citationStress and glucocorticoid modulation of feeding and metabolism
Balsevich, G., Abizaid, A. B., Chen, A., Karatsoreos, I. N., & Schmidt, M. V. (2019) · Neurobiology of Stress · doi:10.1016/j.ynstr.2019.100171 · Cited by 14 · see citing works
Self-citationDNA methylation patterns of FKBP5 regulatory regions in brain and blood of humanized mice and humans
Yusupov, N., Roeh, S., Elliott, L. S., Chang, S., Loganathan, S., Urbina-Treviño, L., Fröhlich, A. S., Sauer, S., Ködel, M., Matosin, N., et al. (2024) · Molecular Psychiatry · doi:10.1038/s41380-024-02430-x · Cited by 12 · see citing works
“In animal models, increased FKBP5 activity in speci fi c, mainly limbic, brain regions has been associated with behaviors indicative of increased anxiety and reduced stress coping [37], while blocking of endogenous FKBP51 resulted in opposite behavioral effects [38 – 40].”
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
Liu, Y., Lian, J., Fu, Y., Wang, S., Liu, Y., Zhang, R., & Han, H. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100762 · Cited by 12 · see citing works
Soto, O. B., Ramirez, C. S., Koyani, R. D., Rodriguez‐Palomares, I. A., Dirmeyer, J. R., Grajeda, B. I., Roy, S., & Cox, M. B. (2023) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30406 · Cited by 13 · see citing works
“123,129 Lack of FKBP51 is found to change the brain structure and connectivity, revealing link among genetic status of FKBP5, stress sensitivity, and psychiatric disorders.”
Yuan, T., Fu, D., Xu, R., Ding, J., Wu, J.-H., Han, Y., & Li, W. (2023) · Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2023.106312 · Cited by 11 · see citing works
Zhang, S., Cheon, M., Park, H.-Y., Kim, T., & Chung, C. (2021) · Neuroscience · doi:10.1016/j.neuroscience.2021.12.020 · Cited by 15 · see citing works
Oakley, R. H., Riddick, N. V., Moy, S. S., & Cidlowski, J. A. (2023) · Neurobiology of Stress · doi:10.1016/j.ynstr.2023.100589 · Cited by 9 · see citing works
“Reductions in the levels or activity of Fkbp5 in the mouse brain have an anxiolytic effect (Attwood et al., 2011; Hartmann et al., 2015), and increased expression of Fkbp5 in humans has been associated with increased risk of developing stress related anxiety disorders (Darby et al., 2016; Klengel…”
BackgroundQiu, B., Zhong, Z., Dou, L., Xu, Y., Zou, Y., Weldon, K. S., Wang, J., Zhang, L., Liu, M., Williams, K. E., et al. (2024) · Cell & Bioscience · doi:10.1186/s13578-023-01184-3 · Cited by 10 · see citing works
“SAFit2 has previously been applied in other studies and no toxicity was demonstrated with long-term treat-ment [46–48].”
FKBP51 and FKBP12.6—Novel and tight interactors of Glomulin
Hähle, A., Geiger, T., Merz, S., Meyners, C., Mao, T.-Q., Kolos, J., & Hausch, F. (2019) · PLoS ONE · doi:10.1371/journal.pone.0221926 · Cited by 8 · see citing works
Self-citationChronic cocaine administration upregulates FKBP5 in the extended amygdala of male and female rats
Connelly, K. L., & Unterwald, E. (2019) · Drug and Alcohol Dependence · doi:10.1016/j.drugalcdep.2019.02.019 · Cited by 8 · see citing works
“, 2014), and reduces anxiety in mice as measured by the elevated plus maze and dark-light box tests (Hartmann et al., 2015).”
BackgroundSUMO conjugation as regulator of the glucocorticoid receptor-FKBP51 cellular response to stress
Liberman, A. C., Budziñski, M. L., Sokn, C., Gobbini, R. P., Ugo, M. B., & ARZT, E. S. (2019) · Steroids · doi:10.1016/j.steroids.2019.108520 · Cited by 7 · see citing works
Hestehave, S., Florea, R., Singleton, S., Fedorec, A. J. H., Caxaria, S., Morgan, O. B., Kopp, K. T., Brown, L. A., Heymann, T., Sikandar, S., et al. (2025) · bioRxiv · doi:10.1101/2024.11.01.621278 · Cited by 6
“This may not be surprising as long-term SAFit2 treatment alone in naïve mice caused anxiety-like behaviour, unlike the acute administration that is known to have anxiolytic effects (11, 12).”
Self-citationZhu, B., Cai, B., Xue, K., Zhou, S., Yin, G., & Fang, J. (2025) · Journal of Cellular and Molecular Medicine · doi:10.1111/jcmm.70552 · Cited by 6 · see citing works
“SAFit2 is a promising compound that modulates stress responses by selectively targeting FKBP5, without affecting the closely related FKBP4 [44–46].”
Kovářová, V., Bordes, J., Mitra, S., Narayan, S. V., Springer, M., Brix, L. M., Deussing, J. M., & Schmidt, M. V. (2024) · Neuropsychopharmacology · doi:10.1038/s41386-024-02008-9 · Cited by 6 · see citing works
Self-citationStramecki, F., Frydecka, D., & Misiak, B. (2020) · Archives of Psychiatry and Psychotherapy · doi:10.12740/app/124985 · Cited by 6 · see citing works
“Animal model studies show that administration of selective inhibitor of the FKBP506-binding protein via microinjections to adrenal gland or intraperitoneal injections results in both reduction of anxiety-related behaviors and increase in active coping behaviors in mice [89, 90].”
BackgroundHäusl, A., Hartmann, J., Pöhlmann, M., Brix, L., Lopez, J., Brivio, E., Engelhardt, C., Roeh, S., Rudolph, L., Stoffel, R., et al. (2019) · bioRxiv · doi:10.1101/824664 · Cited by 6
Self-citationHertzberg, L., Zohar, A. H., & Yitzhaky, A. (2021) · Life · doi:10.3390/life11030190 · Cited by 5 · see citing works
“Moreover, genetic knockout of FKBP5 in mice was shown to increase stress-coping behavior in the forced swim test [13–15] and pharmacological inhibition of FKBP5 was shown to improve stress-coping behaviors in mice [14,52].”
BackgroundA novel role for the immunophilin FKBP52 in motor coordination.
Young, M. J., Geiszler, P. C., & Pardon, M.-C. (2016) · Behavioural Brain Research · doi:10.1016/j.bbr.2016.07.015 · Cited by 5 · see citing works
From intracellular sensors to systemic resilience: Reframing the biology of stress
Hartmann, J. (2025) · Neurobiology of Stress · doi:10.1016/j.ynstr.2025.100755 · Cited by 4 · see citing works
Self-citationJeon, Y.-J., Choi, B., Park, M., Jang, Y.-S., Yoon, S. J., Lyoo, I. K., & Han, J. (2023) · Experimental Neurobiology · doi:10.5607/en23006 · Cited by 5 · see citing works
“Pharmacological inhibition of Fkbp5 improved stress resilience [17, 19, 38].”
BackgroundGabani, B. B., Sulochana, S., Siddesh, A. H. A., Kiran, V., Saini, N., Samanta, S., Hallur, M., Rajagopal, S., & Mullangi, R. (2020) · Drug Research · doi:10.1055/a-1164-6123 · Cited by 4 · see citing works
Hormonal contraceptives modulate resilience to psychiatric and neurodegenerative disease
Schuh, K. M., Conrad, L. M., & Tronson, N. C. (2025) · Hormones and Behavior · doi:10.1016/j.yhbeh.2025.105823 · Cited by 2 · see citing works
SUMO regulation of FKBP51 activity and the stress response
Gobbini, R. P., Velardo, V. G., Sokn, C., Liberman, A. C., & ARZT, E. S. (2023) · Journal of Cellular Biochemistry · doi:10.1002/jcb.30411 · Cited by 3 · see citing works
“14 Consistently, the effects of antidepressants on depressive ‐ like behavior are diminished in FKBP51 knockout mice.”
Zhang, S., Jeon, Y.-J., Han, J., Park, H.-Y., & Chung, C. (2025) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2025.102801 · Cited by 1 · see citing works
Die Bedeutung früher traumatischer Lebenserfahrungen
Overfeld, J., Buß, C., & Heim, C. C. (2016) · InFo Neurologie + Psychiatrie · doi:10.1007/s15005-016-1782-9 · Cited by 3 · see citing works
“Es ist zu erwarten, dass derartige FKBP5-Antagonisten als Antidepressivum eingesetzt werden und speziell Menschen mit genetischer Veranlagung für eine höhere Expression und einer traumaassoziierten Dysregulation der HHNA erfolgreich behandeln können [21].”
BackgroundMatosin, N., Arloth, J., Czamara, D., Edmond, K. Z., Maitra, M., Fröhlich, A. S., Martinelli, S., Kaul, D., Bartlett, R., Curry, A. R., et al. (2021) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2021.01.27.428487 · Cited by 1 · see citing works
Pilatti, F., Philippsen, M., Bertollo, A. G., WEBLER, C. P., Bordignon, A. K., & Ignácio, Z. M. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1801474 · Cited by 1 · see citing works
“These findings, for the first time in vivo , demonstrate the central role of FKBP51 and its potential as a therapeutic target for anxiety disorders (Hartmann et al., 2015).”
Li, C., Huang, J., Ge, H., Si, L., Wu, L., Xie, Y., Xiao, L., & Wang, G. (2026) · The International Journal of Neuropsychopharmacology · doi:10.1093/ijnp/pyag018 · Cited by 1 · see citing works
“Similarly, Hartmann et al. 40 reported that FKBP51 overexpression induces anxiety-like behaviors specifically in the basolateral amygdala.”
FKBP5 regulates interferon signaling leading to myeloid cell activation in multiple sclerosis
Cruz, C. G., Gibson, J., Kita, M., Sankpal, N. V., Piras, I. S., & Cantoni, C. (2026) · Journal of Neuroinflammation · doi:10.1186/s12974-026-03703-8 · Cited by 1 · see citing works
“FKBP5 is a critical co-chaperone of the glucocorticoid receptor (GR) complex, where it modulates stress responsiveness by reducing ligand affinity, delaying GR nuclear translocation, and suppressing glucocorticoid-driven transcriptional activity [11–13].”
Bordes, J., Ji, X., Gasperoni, S., Sudre-Chinsky, C., Kalbasi, A., Harbich, D., Flachskamm, C., Fontanet, P., Narayan, S. V., Uhr, M., et al. (2026) · Advanced Science · doi:10.1002/advs.76040 · Cited by 2 · see citing works
Self-citationKumar, R., Winblad, B. G., & Pavlov, P. F. (2019) · Heat shock proteins · doi:10.1007/978-3-030-23158-3_14 · Cited by 1 · see citing works
FKBP51 inhibition by SAFit2 modulates tau pathology and cognitive deficits in PS19 mice
Contreras-Marciales, A., Mezquite-Garcia, D., Verdina, L. A., Elnahrawy, A., Wolf, T., Guergues, J., Parikh, P., Hunter, E. R., Acosta, D. H., Stevens, S. M., et al. (2026) · Alzheimer s Research & Therapy · doi:10.1186/s13195-026-02107-3
“…the blood-brain barrier up to ~ 16% [24, 28], which has been shown to lower peak corticosterone (CORT) levels [24], improve stress-coping behavior [24, 29], and reduce hypersensitivity to chronic pain in mice [30, 31], as well as prevent stress-induced depressive-like behavior in rats [32].”
Tay, B. Q., Soltau, C. P., Adams, M. N., Bottle, S. E., & Richard, D. J. (2026) · Biochemical Pharmacology · doi:10.1016/j.bcp.2026.118042
FKBP5 splice variant alterations in the human cortex of psychiatric disorders.
Kaul, D., Edmond, K. Z., Czamara, D., Martinelli, S., Ködel, M., Gassen, N., Tao, R., Kleinman, J., Hyde, T., Binder, E., et al. (2026) · Journal of Psychiatric Research · doi:10.1016/j.jpsychires.2026.03.016
Gan, Y., Lin, S. H., Kang, Y.-P., Zhou, J.-Z., Huang, W.-H., Sung, P.-H., Hung, C., Hsu, P.-C., Chu, S.-Y., Shie, F., et al. (2026) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2026.106278
Hestehave, S., Florea, R., Singleton, S., Fedorec, A. J. H., Caxaria, S., Morgan, O. B., Kopp, K. T., Brown, L. A., Heymann, T., Sikandar, S., et al. (2025) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2517405122 · Cited by 5 · see citing works
Self-citationMakrozyklische FKBP51‐Liganden enthüllen einen transienten Bindungsmodus mit erhöhter Selektivität
Voll, A. M., Meyners, C., Taubert, M. C., Bajaj, T., Heymann, T., Merz, S., Charalampidou, A., Kolos, J., Purder, P. L., Geiger, T. M., et al. (2021) · Angewandte Chemie · doi:10.1002/ange.202017352
Self-citationFKBP5 gene expression as a biomarker for treatment outcome in depression
Ising, M. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-817935-2.00026-x
Elucidation of the molecular and cellular mechanisms of FKBP51-selective inhibitors
Haehle, A. (2020) · Technischen Universität Darmstadt · doi:10.25534/tuprints-00013235
“It acted anxiolytic [23,24], protected from weight gain”
Background
- Authors
- Hartmann, J., Wagner, K. V., Gaali, S., Kirschner, A., Kozany, C., Ruhter, G., Dedic, N., Hausl, A. S., Hoeijmakers, L., Westerholz, S., Namendorf, C., Gerlach, T., Uhr, M., Chen, A., Deussing, J. M., Holsboer, F., Hausch, F., & Schmidt, M. V.
- Affiliations
- Max Planck Society (DE)
- Venue
- Journal of Neuroscience
- Publisher
- Society for Neuroscience
- Published
- 2015-06-17
- Volume
- 35
- Issue
- 24
- Pages
- 9007-9016
- ISSN
- 0270-6474 (ISSN-L)
- 1529-2401
- PMC
- PMC6605153
- OpenAlex
- W1758536687
- Cited by
- 109
- References
- 0
- Citations by year
- 2026: 9 · 2025: 9 · 2024: 8 · 2023: 15 · 2022: 9 · 2021: 11 · 2020: 6 · 2019: 18 · 2018: 8 · 2017: 8 · 2016: 7 · 2015: 1
- FWCI
- 4.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Neuroscience (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- FKBP51, anxiety-like behavior, basolateral amygdala, central amygdala, stress sensitivity, gene overexpression, microinjection
- MeSH terms
- Tacrolimus Binding Protein 5, Amygdala, Animals, Anxiety, Ligands, Male, Mice, Inbred C57BL, Microinjections, Risk Factors, Anti-Anxiety Agents, Tacrolimus Binding Proteins, Mice
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