The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder
Haiyin Li, … , Kerry J. Ressler, Fang Liu
Haiyin Li, … , Kerry J. Ressler, Fang Liu
Published January 13, 2020
Citation Information: J Clin Invest. 2020;130(2):877-889. https://doi.org/10.1172/JCI130363.
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Research Article Neuroscience

The glucocorticoid receptor–FKBP51 complex contributes to fear conditioning and posttraumatic stress disorder

Abstract

Posttraumatic stress disorder (PTSD) can develop after exposure to severe psychological trauma, leaving patients with disabling anxiety, nightmares, and flashbacks. Current treatments are only partially effective, and development of better treatments is hampered by limited knowledge of molecular mechanisms underlying PTSD. We have discovered that the glucocorticoid receptor (GR) and FK506 binding protein 51 (FKBP51) form a protein complex that is elevated in PTSD patients compared with unaffected control subjects, subjects exposed to trauma without PTSD, and patients with major depressive disorder (MDD). The GR-FKBP51 complex is also elevated in fear-conditioned mice, an aversive learning paradigm that models some aspects of PTSD. Both PTSD patients and fear-conditioned mice had decreased GR phosphorylation, decreased nuclear GR, and lower expression of 14-3-3ε, a gene regulated by GR. We created a peptide that disrupts GR-FKBP51 binding and reverses behavioral and molecular changes induced by fear conditioning. This peptide reduces freezing time and increases GR phosphorylation, GR-FKBP52 binding, GR nuclear translocation, and 14-3-3ε expression in fear-conditioned mice. These experiments demonstrate a molecular mechanism contributing to PTSD and suggest that the GR-FKBP51 complex may be a diagnostic biomarker and a potential therapeutic target for preventing or treating PTSD.

Authors

Haiyin Li, Ping Su, Terence K.Y. Lai, Anlong Jiang, Jing Liu, Dongxu Zhai, Charlie T.G. Campbell, Frankie H.F. Lee, WeiDong Yong, Suvercha Pasricha, Shupeng Li, Albert H.C. Wong, Kerry J. Ressler, Fang Liu

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Figure 2

Systemic administration of TAT-GRpep reduces freezing behavior.

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Systemic administration of TAT-GRpep reduces freezing behavior. (A and B...
(A and B) GR-FKBP51 complex levels are significantly higher in brain tissues from fear-conditioned mice. Coimmunoprecipitation shows higher levels of the GR-FKBP51 complex in fear-conditioned mouse brain lysate as compared with control (CTRL) mice. (A) Representative Western blot of FKBP51 and GR precipitated by GR antibody. (B) Densitometric analysis of the levels of FKBP51 coimmunoprecipitated by GR antibody in brain lysate of control (CTRL) or fear-conditioned mice. The level of coimmunoprecipitated FKBP51 (FKBP51 Co-IP) was normalized after being divided by the level of precipitated GR (GR IP). Results for each sample are presented as the percentage of control (CTRL). ***P < 0.001 as compared with control samples, n = 7, t test. Data are shown as mean ± SEM. (C) A schematic illustration of the experimental schedule regarding data shown in D. (D) During the 3-minute habituation phase (absence of CS), the animals from both groups displayed a virtual absence of freezing behavior (P = NS). When cues were presented, however, animals in the treatment peptide group froze less than the control peptide (TAT) group (P < 0.05); n = 10. (E) A schematic illustration of the experimental schedule regarding data shown in F. (F) TAT-GRpep reduced cued freezing behavior in mice (P < 0.05); n = 14 (TAT) or n = 13 (TAT-GRpep).