Unlocking the molecular mechanism of PTSD treatment

Post-traumatic stress disorder (PTSD) is a difficult-to-cure mental health condition that is caused by experiencing a traumatizing event, such as interpersonal violence or disaster. While sufferers of PTSD have existed across ...

Currently, various treatment options, such as antidepressants or cognitive behavioral therapy, are used to treat PTSD. Selective serotonin reuptake inhibitors (SSRIs) are the only class of antidepressants that are approved for the treatment of PTSD. However, the medications have drawbacks of delayed action and are not effective in some patients. Cognitive-behavioral therapies, such as eye movement desensitization and reprocessing (EMDR), are also frequently used to treat PTSD. However, such fear extinction therapies are not effective in half of the patients. Moreover, even when the therapy is successful, PTSD is notorious for the recurrence of symptoms. Such relapse of previously treated PTSD is called "spontaneous recovery," which is a subject of many studies.

In the past, studies have pointed out that activities in glutamatergic neurons are an important part of the pathophysiology of PTSD. Particular interest is in the effects of the N-methyl-D-aspartate receptor (NMDAR) on these neurons, which is responsible for controlling synaptic plasticity related to learning and memory . To tackle PTSD at its roots, the researchers from the Center for Cognition and Sociality within the Institute for Basic Science (IBS), in conjunction with Yale University, explored the molecular mechanism of PTSD treatment. In their latest research, published in Molecular Psychiatry , the IBS team tested a PTSD trial drug called NYX-783 in mice and examined the molecular mechanism of its actions. NYX-783 is a newly discovered drug that is known to modulate the NMDAR functions in neurons.

Experimental setup using a mouse model of PTSD. A) auditory fear conditioning model, B) single prolonged stress model, and C) schematic of single prolonged stress inflicted on the animals. Credit: Institute for Basic Science Read more

Experimental data of this study. A) Injection of NYX-783 before the extinction therapy resulted in the successful extinction of PTSD memories and prevented spontaneous recovery. The drug treatment was more effective in female mice, suggesting differential sensitivity of NMDAR modulators in males and females. B) When the activity of endogenous BDNF was blocked in the mouse brain using an antibody, the PTSD memory underwent spontaneous recovery even after successful extinction. When the activity of endogenous BDNF was blocked, NYX-783 injected mice fared no better than those injected with saline. Credit: Institute for Basic Science Read more

Putative molecular mechanism of PTSD treatment. A) In normal mice, NYX-783 acts on the GluN2B subunit of NMDA receptors in glutamatergic neurons, which results in upregulation of BDNF and inhibition of PTSD spontaneous recovery. B) When GluN2B is knocked down in glutamatergic neurons, it eliminated the effectiveness of NYX-783, since the drug no longer has a valid target. C) When GluN2B is knocked down in GABAergic neurons, it lessens the degree of inhibition on the glutamatergic neuron. More glutamate is released, which activates the postsynaptic pyramidal neuron, resulting in a baseline reduction in spontaneous recovery. Credit: Institute for Basic Science Read more