Study reveals key role of TRIO gene in epileptic encephalopathy

What are the molecular and cellular mechanisms by which some babies develop epileptic encephalopathies and autism spectrum disorders? This is what researchers in Canada and France set out to discover and they think they have found the answer.

It turns out that many of these neurodevelopmental disorders are due to a dysfunction in the development of GABAergic interneurons, rare cells in the brain, but whose inhibitory role is crucial to the proper wiring of the cerebral cortex.

In particular, mutations in the TRIO gene disrupt the migration of these interneurons, impairing their ability to integrate properly into circuits and hindering brain development. This is what reveals a new study by Lara Eid, postdoctoral fellow at the University of Montreal, led by Dr. Elsa Rossignol at CHU Sainte-Justine, affiliated with UdeM, with Dr. Evelyne Bloch-Gallego from the Cochin Institute in Paris.

The study appears in Molecular Psychiatry.

A unique technique

After having developed a unique microscopy technique making it possible to follow in real time the movement of interneurons during the embryonic period, the researchers demonstrated that the loss of function of the TRIO gene led to significant difficulties in the migration of interneurons, a key process in the formation of the cerebral cortex.

During normal brain development in an unborn baby, interneurons must leave a deep embryonic structure and travel long distances to reach the developing cortex.

“What we observe in mouse models with an interneuron-specific TRIO deletion is that the affected cells move erratically and more slowly during embryonic development, as if they don’t know where to go,” he said. declared Eid. “This prevents them from reaching their destination, so at the end of migration, many areas of the cortex do not have enough of these interneurons to properly exercise their inhibitory role.

“What we find is that after birth, these models develop a range of cognitive and behavioral disorders not unlike those seen in children with epileptic encephalopathy.”

Trigger morphological changes

The study shows that TRIO plays a key role in integrating signals from the environment and triggering the morphological changes necessary for migrating interneurons to orient themselves and move in the right direction and reach their final destination. These migration difficulties therefore reflect a dysfunction at two levels: in the ability of neurons to change shape to reorient and propel themselves (intrinsic mechanisms) and in their response to external signals (extrinsic mechanisms).

On the one hand, loss of TRIO function alters interneuron morphology and reduces migration speed. On the other hand, this loss means that interneurons respond poorly to attraction or guidance signals secreted by surrounding cells or to certain signals that activate the dynamic migration process.

The new study confirms that these two aspects are absolutely necessary for the normal course of the migration process and that TRIO plays a key role in regulating cellular mechanics through small molecules called Rho GTPases.

Although research has not yet reached the stage of developing a treatment for TRIO-associated epileptic encephalopathy, the study offers promising avenues for the development of pharmacological treatments, gene therapy and cell therapy involving transplantation of GABAergic interneuron progenitor cells.

“Our results suggest that children with TRIO-associated epileptic encephalopathy may benefit from targeted therapy or cell therapy aimed at restoring interneuron number or function,” said Rossignol, co-principal investigator of the study. ‘study. “This data brings us closer to finding a treatment that will improve outcomes for affected children.”