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Increased Methylation of Memory-Related Gene May Decrease Post-Traumatic Stress Disorder Risk

NEW YORK – Methylation of a gene involved in the formation of memories may provide protection against the development of post-traumatic stress disorder, according to a new study.

PTSD is a chronic condition that people may develop following exposure to traumatic events such as disasters, violence, and war, and is marked by re-experiencing the event, avoidance of stimuli associated with the event, and hyperarousal. 

But while many people experience traumatic events, not everyone develops PTSD, leading researchers to examine potential risk factors, including epigenetic factors, for the condition. A University of Basel-led team of researchers examined epigenetic patterns of genes within the glucocorticoid receptor signaling pathway in two populations of traumatized individuals, survivors of the Ugandan civil war and of the Rwandan genocide. Stressful situations activate the hypothalamus-pituitary-adrenal axis and lead to the release of glucocorticoid hormones, which can affect memory processes.

As they reported in the Proceedings of the National Academy of Sciences, Basel's Dominique de Quervain and his colleagues found increased methylation at the NTRK2 gene was associated with decreased PTSD risk. The researchers further found that increased methylation at the NTRK2 gene does not appear to occur in response to trauma, but predates it, and is negatively associated with memory performance among untraumatized individuals.

"The present findings suggest that epigenetic modifications of NTRK2 are involved in memory modulation in health, and in influencing risk and symptoms of PTSD in case of traumatic experiences," de Quervain and his colleagues wrote in their paper.

The researchers collected saliva samples from 463 survivors of the Ugandan civil war and from 350 survivors of the 1994 Rwandan genocide for methylation analysis using Illumina's EPIC BeadChip or Infinium 450K methylation array. The researchers examined methylation at regional elements involved in regulating the glucocorticoid receptor signaling pathway in conjunction with symptoms and signs of PTSD.

In their discovery cohort of Ugandan individuals, they found links between the methylation of four genes in the RGRS pathway and PTSD risk: NTRK2, CLOCK, NR3C1, and NCOA2. They then confirmed the link between methylation at NTRK2 and PTSD risk in the Rwandan cohort. In particular, increased methylation at NTRK2 was associated with decreased PTSD risk.

NTRK2 encodes the transmembrane receptor tropomyosin-related kinase B (TrkB), which binds the brain-derived neurotrophic factor (BDNF) and other neurotrophic factors. BDNF signaling is involved in memory consolidation and BDNF-TrkB signaling through Erk1/2MAPK phosphorylation is involved in the glucocorticoid-induced enhancement of fear memory. NTRK2 has also been tied to a number of psychiatric conditions, the researchers noted.

As NTRK2 methylation was not linked to individuals' traumatic load, the researchers found that methylation levels at NTRK2 appeared to be set prior to the experience of a traumatic event and not as its result.

However, they did find a link between methylation at NTRK2 and memory performance. In a cohort of 568 untraumatized Swiss individuals, the researchers uncovered a negative association between NTRK2 methylation and an assessment of memory performance. Through a functional MRI-based analysis, they further found altered brain activity in individuals with increased methylation.

The findings suggested to the researchers that increased NTRK2 regulation reduces memory formation so that traumatic experiences are not as well remembered, thus decreasing PTSD risk.

"[T]his study demonstrates that epigenetic differences in NTRK2 are related to memory functions in healthy nontraumatized subjects and to traumatic memory and PTSD risk in traumatized individuals," the researchers wrote in their paper.

As the TrkB receptor is a druggable target — in animals, a TrkB antagonist has been found to reduce anxiety — the researchers added that this work might help uncover new PTSD therapies.

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