Olivia Lennon

Background: Post-traumatic stress disorder (PTSD) is a chronic psychiatric disorder that can develop after exposure to a traumatic event or stressor.¹ Approximately 10% of trauma-exposed individuals will develop PTSD.^1,2 Certain groups have higher prevalence such as combat veterans and victims of rape with rates up to 20% and 50%, respectively.² Currently, treatment involves trauma-focused psychotherapy and pharmacologic therapy that mainly target symptom reduction, but remission rates are only 20-30%.^2,3 The sizeable portion of patients who fail to respond to treatment indicates a need for research on biological targets for diagnosis and prevention and has led to a search for biomarkers to improve PTSD treatment.² Although the development of PTSD is believed to involve environmental and genetic factors, dysregulation of the Hypothalamic Pituitary Adrenal (HPA) Axis has been largely proven to play a role in the disorder.^1,3,4 MicroRNAs regulating FKBP5, a gene involved in HPA Axis function, have recently received focus for their potential as diagnostic markers in PTSD-susceptible individuals.⁵ These findings may pose a novel means of improving PTSD recognition and early treatment.

Objective: We reviewed the mechanisms by which FKBP5 modulates stress response in PTSD and the role of microRNA biomarkers in identifying PTSD phenotype.

Search Methods: An online search was conducted using the PubMed database with results restricted to years 2018 to 2024 and using the MeSH term “stress disorders, post-traumatic.” Results were then screened for mention of “FKBP5” and “microRNA.”

Results: Studies indicate that PTSD-phenotype rats have higher levels of corticosterone suppression in response to a methylprednisolone stress test than normal-phenotype rats.⁶ Moreover, PTSD-phenotype rats demonstrated increased FKBP5 gene expression in the hypothalamus and prefrontal cortex that negatively correlated with PTSD-symptom scores.⁶ FKBP5 knockout mice lacked an anhedonia response to chronic restraint stress, similar to mice unexposed to a stressor.⁷ Elevated FKBP5 levels were observed in the prefrontal cortex and hippocampus of PTSD-phenotype rats exposed to a chronic unpredictable mild stress model.⁸ The markers miR-124a and miR-18a were found to have a significant correlation with FKBP5 and GR levels in these brain regions as well.⁸ One animal model of PTSD identified PTSD-susceptible mice based on their arousal scores following a stress test. In this study, there was a negative correlation between miR-15a-5p and miR-511-5p and arousal scores, and a positive correlation between FKBP5 elevation and arousal scores.⁹ Circulating exosomal miRNA composite markers in human serum, first identified in FKBP5 knockout mice, were successful in identifying a positive PTSD diagnosis in trauma-exposed individuals as opposed to trauma-exposed individuals who did not develop PTSD.⁵ Moreover, the composite markers were able to identify the severity of PTSD symptoms, using the Clinician-Administered Posttraumatic Stress Disorder Scale for DSM-5.⁵

Conclusions: Studies have found that FKBP5 elevation leads to an altered stress response in PTSD animal models. Certain microRNAs have been shown to epigenetically regulate FKBP5 expression, thereby modulating HPA axis activity. Further research on circulating miRNAs may be used for early detection of PTSD in trauma-exposed individuals to support early intervention and improved treatment outcomes.

Works Cited:

1. Gupta S, Guleria RS, Szabo YZ. MicroRNAs as biomarker and novel therapeutic target for posttraumatic stress disorder in Veterans. Psychiatry Research. 2021/11/01/ 2021;305:114252. doi:https://doi.org/10.1016/j.psychres.2021.114252
2. Dunlop BW, Wong A. The hypothalamic-pituitary-adrenal axis in PTSD: Pathophysiology and treatment interventions. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2019/03/08/ 2019;89:361-379. doi:https://doi.org/10.1016/j.pnpbp.2018.10.010
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5. Kang HJ, Yoon S, Lee S, et al. FKBP5-associated miRNA signature as a putative biomarker for PTSD in recently traumatized individuals. Sci Rep. Feb 25 2020;10(1):3353. doi:10.1038/s41598-020-60334-6
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8. Xu J, Wang R, Liu Y, et al. Short- and long-term alterations of FKBP5-GR and specific microRNAs in the prefrontal cortex and hippocampus of male rats induced by adolescent stress contribute to depression susceptibility. Psychoneuroendocrinology. Mar 2019;101:204-215. doi:10.1016/j.psyneuen.2018.11.008
9. Maurel OM, Torrisi SA, Barbagallo C, et al. Dysregulation of miR-15a-5p, miR-497a-5p and miR-511-5p Is Associated with Modulation of BDNF and FKBP5 in Brain Areas of PTSD-Related Susceptible and Resilient Mice. Int J Mol Sci. May 13 2021;22(10)doi:10.3390/ijms22105157