generalized fear underpinned by a cerebral transporter ⋅ Inserm, La science pour la santé

Post-traumatic stress disorder affects people who have been exposed to extremely stressful situations. It leads to an alteration in their ability to manage their emotions and can induce an almost permanent feeling of fear. A Parisian research team has just shown that, in mice, a protein present in certain neurons in the brain regions involved in memory and fear, the transporter VGLUT3, could play an important role in this disorder.

The VGLUT3 protein could well be a new therapeutic target to fight against the appearance of generalized aversive fears, such as those which characterize post-traumatic stress disorders. Some people exposed to particularly stressful or traumatic situations develop a generalized fear that paralyzes them in contexts that are not a priori anxiety-provoking. This phenomenon constitutes a significant handicap, which leads them to modify their habits and their behavior so as not to find themselves paralyzed by fear on a daily basis. Their management is now based on psychotherapies, often associated with drugs (sedatives, antidepressants, anxiolytics) whose effectiveness is however limited. Having drug treatments with more specific action could be a game-changer for patients. And this is precisely what the work carried out by Stéphanie Daumas’ team at the Paris-Seine Biology Institute could lead to.

This team specializes in the study of VGLUT proteins, transporters that allow a neurotransmitterthe glutamate, inside neurons. Among them, VGLUT3 is atypical because it is expressed by neurons initially described as not using glutamate to communicate with other nerve cells, which raises questions for the researchers. In previous work, the team has shown that anomalies in its expression in the striatum, a region of the brain that notably regulates motivation and impulses, are associated with psychiatric disorders such as addiction or anxiety. . VGLUT3 is also expressed in a subset of neurons in the amygdala and hippocampus, two regions involved in memory and fear. Also, the team wanted to “dissect” the different categories of memory potentially affected by the absence of VGLUT3.

No memory problems but an irrational fear

To do this, the researchers subjected mice to various tests, whether or not they had a deficiency in VGLUT3. During the first experiments, the animals simply had to memorize places or objects. On these tasks, mice deficient in VGLUT3 performed as well as the others, so that the researchers concluded that the transporter was not involved in normal memory processes. In a second step, the researchers put the animals in a stressful situation. And there, the role of VGLUT3 proved decisive. It appeared that when they receive an electric shock to the legs, animals lacking VGLUT3 develop generalized fear. Following this experience, they were paralyzed by any new environment. ” In labsence of VGLUT3, we observe a potentiation of fear, one of the symptoms of post-traumatic stress “, clarifies Stéphanie Daumas. Another important observation is that the acquisition of this generalized fear is reversible: experiences of dissociation from fear and lived situations, on the model of cognitive behavioral therapies offered to patients, allowed the mice to return to a normal emotional state.

The team is now seeking to understand the exact role of this transporter in the brain dysfunctions that lead to generalized fear. In parallel, she is developing molecules capable of binding to VGLUT3 to modify its activity. This work could eventually lead to the development of new treatments.

Stéphanie Daumas heads the Neuropharmacology of VGLUTs team