Image Courtesy of Michael Clesle.
Around six percent of the US population will experience post-traumatic stress disorder (PTSD) at some point in their lifetime. Marked by symptoms such as involuntary flashbacks and severe mood changes, PTSD is twice as likely to affect women than men, although the reason for this is unknown. A recent study conducted by the Esterlis lab at the Yale School of Medicine offers promising insights for understanding the mechanisms underlying differences in susceptibility to PTSD.
Metabotropic glutamate receptor 5 (mGlu5), a receptor found in neurons, is correlated with the presence of PTSD, meaning that individuals with PTSD tend to have higher levels of mGlu5. “The question [we] had was if mGlu5 was a risk factor or if it developed after PTSD,” said Ruth Asch, a post-doctoral researcher in the Esterlis lab. If mGlu5 receptors were found to be a causal factor, they might serve as a potential pathway to a cure. Alternatively, if mGlu5 receptors were produced as a result of the condition’s progression, they might offer a new method for treating symptoms. How could the scientists prove this? After all, a rat can’t explain that it is suffering from PTSD. “We can look at different things in these animals that relate to a specific domain within the diagnosis, like heightened hypervigilance, pain sensitivity, enhanced fear learning,” Asch said. She further emphasized that although rats cannot be equated to human subjects, findings from experiments with animal models can help determine novel targets for research and indicate which therapies have potential.
The team’s experimental method involved an electric shock serving as a ‘traumatic event.’ The researchers then measured the change in participants’ fear response before and after the shock, measuring males and females separately. The results suggested the mGlu5 receptor was indeed a causal factor in PTSD. The researchers also found that mGlu5 receptor availability levels were higher for male rats compared to female rats, suggesting that mGlu5 may be an underlying factor in increased female susceptibility to PTSD in humans.
What does this imply for clinical outcomes? “It suggests that mGlu5 has a role in fear learning, and also learning [in general],” Asch said. By identifying mGlu5 as a potential target, this knowledge could help us prevent the extreme fear learning that leads to PTSD. According to Asch, specific parts of the mGlu5 signal cascade can be selectively blocked to prevent bad learning while still maintaining beneficial learning. The valuable conclusions drawn from this study are not to be taken for granted either—Esterlis’s lab had suffered its fair share of setbacks, including a temporary shutdown due to the COVID-19 pandemic. Asch is optimistic that further research will lead to a deeper understanding of what exactly causes PTSD. “Psychiatry is moving more toward, ‘Can we understand what’s driving these symptoms?’” Asch said. Perhaps the mGlu5 receptor will be the key to this understanding.