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 February 3, 2020; First 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 5

Higher GR-FKBP51 complex levels, decreased GR S211 phosphorylation, and reduced nuclear GR in peripheral blood of PTSD patients.

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Higher GR-FKBP51 complex levels, decreased GR S211 phosphorylation, and ...
(A–B) Representative Western blots (A) and densitometric analysis (B) of the levels of GR (left), FKBP51 (right) coimmunoprecipitated by FKBP51 antibody in peripheral blood samples from PTSD patients and healthy controls. Results for each sample are presented as the percentage of the mean of the control samples on the same blot. CTRL: 1 ± 0.069, PTSD: 1.408 ± 0.641, ***P < 0.001, n = 22, t test. (C) Densitometric analysis of the levels of GR (left), FKBP51 (right) coimmunoprecipitated by FKBP51 antibody in peripheral blood samples from PTSD patients and trauma controls. Results are presented as the percentage of trauma controls on the same blot. Trauma: 1 ± 0.061, PTSD: 1.455 ± 0.661, ***P < 0.001, n = 21, t test. (D) Densitometric analysis of the levels of GR (left), FKBP51 (right) coimmunoprecipitated by FKBP51 antibody in peripheral blood samples from MDD patients and healthy controls. Results are presented as the percentage of healthy controls on the same blot; P = 0.7768, n = 23, t test. (E) Densitometric analysis shows decreased GR phosphorylation at S211 in lymphocytes from PTSD patients compared with healthy controls (CTRL); **P < 0.01, n = 18, t test. (F) Densitometric analysis of levels of nuclear expression of GR in lymphocytes from PTSD patients and healthy controls (CTRL); **P < 0.01, n = 12, t test. (G) FKBP51 binding inhibits nuclear translocation of GR. Reduced nuclear translocation of GR is negatively correlated with higher GR-FKBP51 complex levels in lymphocytes from PTSD patients compared with CTRL; n = 24 (12 PTSD and 12 CTRL), Pearson correlation coefficient r = –0.44392, P = 0.03. (H–I) Representative Western blots (H) and densitometric analysis (I) of levels of 14-3-3ε expression in lymphocytes from PTSD patients and healthy controls (CTRL). Results are presented as the percentage of the mean of the control samples on the same plot. **P < 0.01, n = 21, t test. Data are shown as mean ± SEM.