Glucocorticoid-induced leucine zipper “quantifies” stressors and increases male susceptibility to PTSD

Maya A. Lebow, Mariana Schroeder, Michael Tsoory, Dorin Holzman-Karniel, Divya Mehta, Shifra Ben-Dor, Shosh Gil, Bekh Bradley, Alicia K. Smith, Tanja Jovanovic, Kerry J. Ressler, Elisabeth B. Binder, Alon Chen

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

Post-traumatic stress disorder (PTSD) selectively develops in some individuals exposed to a traumatic event. Genetic and epigenetic changes in glucocorticoid pathway sensitivity may be essential for understanding individual susceptibility to PTSD. This study focuses on PTSD markers in the glucocorticoid pathway, spotlighting glucocorticoid-induced leucine zipper (GILZ), a transcription factor encoded by the gene Tsc22d3 on the X chromosome. We propose that GILZ uniquely “quantifies” exposure to stressors experienced from late gestation to adulthood and that low levels of GILZ predispose individuals to PTSD in males only. GILZ mRNA and methylation were measured in 396 male and female human blood samples from the Grady Trauma Project cohort (exposed to multiple traumatic events). In mice, changes in glucocorticoid pathway genes were assessed following exposure to stressors at distinct time points: (i) CRF-induced prenatal stress (CRF-inducedPNS) with, or without, additional exposure to (ii) PTSD induction protocol in adulthood, which induces PTSD-like behaviors in a subset of mice. In humans, the number of traumatic events correlated negatively with GILZ mRNA levels and positively with % methylation of GILZ in males only. In male mice, we observed a threefold increase in the number of offspring exhibiting PTSD-like behaviors in those exposed to both CRF-inducedPNS and PTSD induction. This susceptibility was associated with reduced GILZ mRNA levels and epigenetic changes, not found in females. Furthermore, virus-mediated shRNA knockdown of amygdalar GILZ increased susceptibility to PTSD. Mouse and human data confirm that dramatic alterations in GILZ occur in those exposed to a stressor in early life, adulthood or both. Therefore, GILZ levels may help identify at-risk populations for PTSD prior to additional traumatic exposures.

Original languageEnglish
Article number178
JournalTranslational Psychiatry
Volume9
Issue number1
DOIs
StatePublished - 25 Jul 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s).

Funding

A.C. is the head of the Max Planck Society–Weizmann Institute of Science Laboratory for Experimental Neuropsychiatry and Behavioral Neurogenetics. M.T. is the Carolito Stiftung Research Fellow Chair in Neurodegenerative Diseases (MT). We thank Mr. Sharon Ovadia for his devoted assistance with animal care. This work is supported by: an FP7 Grant from the European Research Council (260463, A.C.); a research grant from the Israel Science Foundation (1565/15, A.C.); the ERANET Program, supported by the Chief Scientist Office of the Israeli Ministry of Health (3–11389, A.C.); the project was funded by the Federal Ministry of Education and Research under the funding code 01KU1501A (A.C.); research support from Roberto and Renata Ruhman (A.C.); research support from Bruno and Simone Licht; I-CORE Program of the Planning and Budgeting Committee and The Israel Science Foundation (grant no. 1916/12 to A.C.); the Nella and Leon Benoziyo Center for Neurological Diseases (A.C.); the Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics (A.C.); the Perlman Family Foundation, founded by Louis L. and Anita M. Perlman (A.C.); the Adelis Foundation (A.C.); the Marc Besen and the Pratt Foundation (A.C.); and the Irving I. Moskowitz Foundation (A.C.). The human studies were supported by the Behrens-Weise Foundation (E.B.B); National Institute of Mental Health Grants MH071537 (to K.J.R.), HD071982 (to B.B.), MH100122 (to T.J.), and MH085806 (to A. K.S.). We thank Maik Ködel and Anne Löschner for their technical support.

FundersFunder number
Behrens-Weise Foundation
Henry Chanoch Krenter Institute for Biomedical Imaging and Genomics
Irving I. Moskowitz Foundation
Marc Besen
Nella and Leon Benoziyo Center for Neurological Diseases
Roberto and Renata Ruhman1916/12
National Institute of Mental HealthMH100122, MH071537, MH085806
National Institute of Child Health and Human DevelopmentR01HD071982
Achelis Foundation
Seventh Framework Programme
FP7 Ideas: European Research Council
Pratt Foundation
Perlman Family Foundation
European Research Council260463
Bundesministerium für Bildung und Forschung01KU1501A
Israel Science Foundation1565/15
Ministry of Health, State of Israel3–11389

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