A research team headed by scientists at the University of Basel has linked epigenetic regulation of a gene, NTRK2, which is involved in glucocorticoid receptor signaling, with a reduced risk of developing post-traumatic stress disorder (PTSD) among survivors of war, or genocide in Africa. Reporting their research in the Proceedings of the National Academy of Sciences (PNAS), the researchers suggest their findings could ultimately lead to the development of new approaches to reducing traumatic memories. “These results might contribute to a better understanding of the pathogenesis of PTSD, ultimately paving the way for the discovery of novel biomarkers and drug targets,” they concluded. Research lead Dominique de Quervain, MD, and colleagues in Switzerland, Germany, and the U.S., report their discoveries in a paper titled, “NTRK2 methylation is related to reduced PTSD risk in two African cohorts of trauma survivors.”
Traumatic experiences, such as a serious accident, rape or torture, can become deeply entrenched in memory and cause symptoms of post-traumatic stress disorder, perhaps years later. “Post-traumatic stress disorder (PTSD) is a chronic pathological response to a traumatic event and characterized by re-experiencing of the traumatic event, avoidance of stimuli associated with the trauma, negative alterations in cognition and mood, and hyperarousal,” the team explained. Individuals with PTSD may have symptoms including intrusive daytime recollections of the event, traumatic nightmares, and flashbacks.
The stress hormone cortisol plays a vital role in the regulation of these memory processes, as demonstrated by a number of studies, including those from the University of Basel team. “Extensive pharmacologic, genetic, and epigenetic research has linked the glucocorticoid receptor (GR) to memory processes, and to risk and symptoms of post-traumatic stress disorder,” the investigators commented.
Their previous studies had found that increased DNA methylation at a particular site of the GR gene promoter was linked with less intrusive memory of the traumatic event, and reduced PTSD risk in survivors of the Rwandan genocide. The link was independent of the trauma load, “suggesting that the epigenetic changes pre-existed the trauma,” they wrote.
For their newly reported work de Quervain’s team continued to take a closer look at the genes involved in cortisol signaling. “In the present study, we further examined the association between epigenetic modification of glucocorticoid signaling and PTSD by expanding our analysis to the genes involved in the regulation of GR signaling (RGRS) pathway in two independent samples of severely traumatized individuals,” they wrote. To do this Vanja Vukojevic, PhD, one of the lead authors of the study, analyzed DNA methylation in two groups of people affected by trauma; 463 survivors of the Ugandan civil war, and 350 survivors of the genocide in Rwanda.
The results showed that in both groups, individuals who showed stronger regulation of the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene were at a reduce risk of developing PTSD. The researchers were also able to rule out with a high degree of certainty that the trauma itself leads to an altered regulation of this gene. They found no link between the severity of the trauma and the extent of DNA methylation, which indicated that the level of DNA methylation existed before the traumatic experience. “Importantly, methylation of the NTRK2 regional element was independent of the trauma load, suggesting that methylation differences pre-existed traumatic events.”
Several basic studies have already shown that the gene NTRK2 plays a key role in memory formation. NTRK2 encodes the transmembrane receptor tropomyosin-related kinase B (TrkB). This receptor binds brain derived neurotrophic factor (BDNF) as well as other neurotrophic factors, the investigators further explained. “Among its involvements in promoting neuronal survival and development, BDNF signaling has been shown to play an important role in memory consolidation through long-term potentiation induction,” they commented. “Importantly, BDNF-TrkB signaling through Erk1/2MAPK phosphorylation mediates the enhancement of fear memory induced by glucocorticoid.”
Interestingly, human genetics studies have linked NTRK2 with a range of psychiatric conditions, including attempts at suicide in depressed patients, obsessive-compulsive disorder, anxiety, and mood disorder. “However, to our knowledge there are no studies on epigenetic modifications of NTRK2 with regard to PTSD or learning and memory,” they further wrote.
The researchers were able to link the epigenetic regulatory mechanism—DNA methylation on the gene NTRK2—with memory in 568 non-traumatized individuals. “… we found that increased methylation of NTRK2 was associated with reduced memory in nontraumatized individuals.” Interestingly, people with stronger methylation of the gene performed worse when it came to remembering images they had seen previously. Studies also showed altered brain activity in regions important for memory during the tests.
The combined results of the studies suggest that increased regulation of the NTRK2 gene reduces memory formation. As a result, traumatic experiences do not become as entrenched in the memory, reducing the risk of developing PTSD. The researchers hope that this mechanism will contribute to the development of new therapies, which may also help in cases of existing PTSD by preventing recurrent unpleasant recollections from further cementing the traumatic memory.
“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,” the team concluded. “Thus, if a traumatic event is experienced by an individual with a high level of NTRK2 methylation, it is possible they may form a less traumatic memory and therefore have a reduced risk of developing PTSD.”
