In any given year, just over five million Americans are diagnosed with post-traumatic stress disorder (PTSD).  This mental abnormality is caused by exposure to a severe or traumatic event.  Most trauma-exposed individuals develop a normal response to alarming stressors by adapting and extinguishing the feelings or sensation of fear.  However, about 10% of individuals who are subject to trauma develop prolonged and irregular reactions to these situations known as “abnormal fear extinction.” Symptoms of avoidance, arousal, and flashbacks pervade the everyday routine of those diagnosed with the disorder.

Fear extinction learning involves the ability to reduce the physical and mental response to fear, and provides a measurable dimension for the study of PTSD as deficits in this extinction learning underlie its development.  Countless translational research studies have traced the response to traumatic stress to the anomalous activity of the hypothalamic-pituitary-adrenal (HPA) axis, which is a negative-feedback, stress-response system that functions in locations such as the amygdala.  More specifically, abnormalities in cortisol feedback in glucocorticoid receptors (GR) contribute to this characteristic impaired fear extinction.  GR hypersensitivity can effectively dysregulate the HPA axis, contributing to improper fear extinction in PTSD patients.  Despite this molecular understanding of the contributions to PTSD, treatments for this illness are currently lacking.  The only medications available are selective serotonin reuptake inhibitors (SSRIs), affecting the serotonin neurotransmitter to regulate mood, appetite, sleep, and functioning as an antidepressant.  However, this class of drugs has many side effects, and yields remission in only 20% of patients.  Therefore, the regulation of the HPA axis through glucocorticoid receptors provides an exciting opportunity for the treatment PTSD.

Scientists under the direction of Raül Andero from Emory University School of Medicine identified dexamethasone, a GR receptor agonist that suppresses the HPA axis due to negative feedback, as a treatment for enhanced fear extinction.  The research team investigated the regulation of the GR and the connection between HPA axis activation and stressful situations.  Particularly, the study turned to the genetic instructions for the cortisol feedback system, in which PTSD originates.  Andero investigated how modification in expression of the FKBP5 gene could improve fear extinction learning.  The FKBP5 gene encodes a binding protein that monitors and regulates the GR sensitivity and the HPA axis, which plays a critical role in the mammalian response to stress.  In addition, a correlation was found between the gene and a predisposition for developing PTSD.

Andero and colleagues were the first to demonstrate that dexamethasone-mediated suppression of the HPA axis prior to extinction learning led to increased regulation of the FKBP5 protein in the amygdala and increased extinction of fear introduced in mice.  It was concluded that regulation of FKBP5 gene expression in the amygdala and its consequential regulation of GR sensitivity could be the molecular mechanism of fear extinction.

In a further study of the dexamethasone agonist, a cross-species study in fear extinction learning was performed by a group of scientists at the New York University School of Medicine.  The study focuses on how a FK506 binding protein regulates cortisol binding to the GR.  Activation of the FK506 protein induces FKBP5 transcription and protein expression, reducing the likelihood of PTSD-related symptoms.  In humans, researchers tested the correlation of FKBP5 single nucleotide polymorphisms (SNPs), or variations in a single base pair in a DNA sequence, and PTSD symptoms with abnormal extinction phenotypes.  The team found that SNPs in FKBP5 associated with PTSD risk, were associated with abnormal extinction learning with tests involving mice. Individuals with FKBP5 mutations demonstrated PTSD symptoms at a greater frequency.

In mice, the investigators tested if increasing doses of dexamethasone given before extinction behavior would alter fkpb5 mRNA expression in the amygdala after extinction and recall, consequently preventing the development of abnormal extinction phenotypes.  The researchers found that administration of high-dose dexamethasone enhanced FKBP5 gene transcription in the amygdala, reducing abnormal fear extinction among the aforementioned individuals.  The higher dose of dexamethasone bypassed the blood-brain barrier more than smaller doses, and therefore had a greater influence on the GR receptors’ sensitivity.  The study concluded that the higher dosage of dexamethasone, 300 μL/kg (administered prior to extinction), was involved with intensified amygdala fkpb5 mRNA transcription following extinction, including enhanced extinction learning.  Overall, this study conclusively suggests that the FKBP5 gene is a viable target for treating PTSD.s

The conclusions made by these two studies show a promising future for the development of PTSD treatments.  Adults, teens, veterans, and others experiencing abnormal responses to traumatic scenarios could likely benefit from these findings, although research continues to confirm the safety, effectiveness, and availability of the treatment.  As current treatments involving less molecular alterations continue to be applied, the implications of this study encourage an outlet for neurobiological intervention that can increase effectiveness and biological specificity for the disorder.


REFERENCES

  1. Alexander, W. (2012). Pharmacotherapy for Post-traumatic Stress Disorder In Combat Veterans: Focus on Antidepressants and Atypical Antipsychotic Agents. Pharmacy and Therapeutics37(1), 32–38.
  2. Galatzer-Levy, I. R., Andero, R., Sawamura, T., Jovanovic, T., Papini, S., Ressler, K. J., & Norrholm, S. D. (2016). A cross species study of heterogeneity in fear extinction learning in relation to FKBP5 variation and expression: Implications for the acute treatment of posttraumatic stress disorder. Neuropharmacology, 116, 188-195. Retrieved March 1, 2017, from http://www.sciencedirect.com/science/article/pii/S0028390816305883
  3. Sawamura, T. Klengel, A. Armario, T. Jovanovic, S.D. Norrholm, K.J. Ressler, & R. Andero. (2016). Dexamethasone treatment leads to enhanced fear extinction and dynamic Fkbp5 regulation in amygdala. Neuropsychopharmacology, 41, 832–846. Retrieved March 1, 2017, from https://www.scopus.com/record/display.uri?eid=2-s2.0-84954027299&origin=inward&txGid=50E9DCDB1F8A61CE4735C14FD50907DC.wsnAw8kcdt7IPYLO0V48gA%3a2
  4. The National Institute of Mental Health. (2016, February). Post-Traumatic Stress Disorder. Retrieved March 1, 2017, from https://www.nimh.nih.gov/health/topics/post-traumatic-stress-disorder-ptsd/index.shtml#part_145375

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