Unlocking the molecular mechanism of PTSD treatment
Scientists discover that modulating NMDA receptor activity is the key to successful treatment

Date:
April 14, 2022
Source:
Institute for Basic Science
Summary:
Unlocking the molecular mechanism of PTSD treatment. Scientists
discover that modulating NMDA receptor activity is the key to
successful treatment.



FULL STORY ========================================================================== 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 all of human history and the condition is even observed
in animals, the diagnosis of this condition only appeared in the 1970s
after the Vietnam War.

PTSD patients are widely known to suffer from various symptoms from
recurring flashbacks, anxiety, and negative alteration in cognition.


========================================================================== 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 by 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.

There are two established rodent models of PTSD: auditory fear
conditioning (AFC) and single-prolonged stress (SPS) models. For
auditory fear conditioning, the mice were habituated to an environment
and subjected to a combination of a tone and electric shock for fear conditioning to induce PTSD. To induce single prolonged stress, some of
the mice were exposed to multiple stressors to induce single prolonged
stress before the fear conditioning. It should be noted that stressful experience before fear conditioning is well known to cause further
difficulties in PTSD treatment later on.



==========================================================================
The mice were then placed in a new environment and subjected to a series
of memory extinction procedures in an attempt to remove their traumatic memories.

To augment the cognitive behavioral therapy, the researchers tested the performance of NYX-783 alongside ketamine, which is a known rapid-acting antidepressant medication. It was discovered that injecting the mice
with the drug 1 hour before fear extinction therapy resulted in the
highest success rate of treatment.

After the treatment, the mice were monitored for freezing behavior upon
hearing the same sound in order to measure the level of fear that they
are experiencing. It was confirmed that mice injected with NYX-783 fared
much better than those injected with ketamine or saline controls. The
drug was particularly effective in suppressing spontaneous recovery,
or unwanted return of PTSD. The drug behaved differently depending on
the gender of the mice, with female mice responding more positively to treatment than male mice.

To explore the mechanism of the treatment, these experiments were repeated
in conjunction with genetic manipulation. First, it was discovered that
NYX-783 inhibits fear memories and suppresses spontaneous recovery of
those memories by modulating NMDA receptors, specifically by acting on
the GluN2B subunit. In order to test this, the researchers knocked down
the GluN2B subunit of NMDARs by manipulating the Grin2b gene using viral vectors. As expected, the efficacy of the drug mostly diminished when
the receptors were knocked down in glutamatergic neurons in the medial prefrontal cortex. In particular, the Grin2b knockdown mutant exhibited spontaneous recovery, even if it was injected with NYX-783.

On the other hand, the performance of the drug was not affected when the
same receptors were knocked down in GABAergic interneurons. Interestingly,
it was found that knocking down the NMDA receptors in the interneurons
alone was capable of reducing spontaneous recovery. The group believed
this is most likely through reducing the interneuron's inhibitory effects
on the main neuron.

However, this doesn't entirely preclude the possibility of NYX-783 acting
on the inhibitory interneurons. The authors noted, "Grin2b knockdown in interneurons without NYX-783 already shows low freezing during spontaneous recovery. Because of this floor effect, we may not see a further reduction
in freezing with NYX-783 during spontaneous recovery even if NYX-783
acts via GluN2B on glutamatergic neurons." While it is believed that
the drug's activity on the glutamatergic neuron is more important for behavioral output, more research may be necessary to confirm this.

Lastly, the team found that brain-derived neurotrophic factor (BDNF),
which is highly important for synaptic plasticity, is necessary for the extinction of memory. When the authors suppressed BDNF activity in mice
brains using antibody treatment, it blunted most of the effect of NYX-783
on inhibition of spontaneous recovery.

Corresponding author LEE Boyoung from the Center for Cognition and
Sociality commented, "Together, these findings suggest that NYX-783,
a novel NMDAR positive modulator, may be an effective medication for
PTSD. Although clinical studies of this compound are ongoing, these
findings suggest that the development of NMDAR modulators may be a viable strategy to treat PTSD."

========================================================================== Story Source: Materials provided by Institute_for_Basic_Science. Note:
Content may be edited for style and length.


========================================================================== Journal Reference:
1. Boyoung Lee, Santosh Pothula, Min Wu, Hyeyeon Kang, Matthew
J. Girgenti,
Marina R. Picciotto, Ralph J. DiLeone, Jane R. Taylor, Ronald
S. Duman.

Positive modulation of N-methyl-D-aspartate receptors in the mPFC
reduces the spontaneous recovery of fear. Molecular Psychiatry,
2022; DOI: 10.1038/s41380-022-01498-7 ==========================================================================

Link to news story: https://www.sciencedaily.com/releases/2022/04/220414110855.htm

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