Understanding One Gene’s Role in Different Neurodevelopmental Disorders

Researchers have identified how variations in a gene called TRIO can influence brain functions and result in distinct neurodevelopmental diseases. The study, published in the journal eLife, could pave the way for future therapeutic developments.

TRIO encodes a diverse group of proteins that control the function and structure of the cytoskeleton—a cell’s internal scaffolding. Rare damaging variants in this gene have been identified in individuals with intellectual disability, autism spectrum disorder, schizophrenia, and related disorders. However, the mechanisms underlying the associations aren’t yet understood.

“It's really extraordinary that different variants in this single gene can have such dramatically different effects on brain development and function,” says Anthony Koleske, PhD, Ensign Professor of Molecular Biophysics and Biochemistry at Yale School of Medicine (YSM) and the study’s senior author.

To better understand this gene’s impact, Koleske and his team investigated how three variants of TRIO—K1431M, seen in individuals with autism spectrum disorder, K1918X in schizophrenia, and M2145T found in an individual with bipolar disorder—affected the brain sizes, behaviors, and neuronal activity of mice.

Patients who carry certain mutations of TRIO not only display neurodevelopmental impacts, such as autism and intellectual disability, but their head circumferences also tend to be smaller than is typical, explains Amanda Jeng, an MD-PhD candidate at YSM and co-first author of the study. “We wanted to see if that was the case in mice as well,” she says.

The researchers bred female and male mice with three different variants of TRIO with mice that had the typical version of the gene. This crossbreeding yielded offspring that had two different versions of the gene—one from each parent—mimicking what occurs in humans.

Indeed, as in humans with variants in one copy of the TRIO gene, the researchers found that mice with K1431M (autism-associated) and K1918X (schizophrenia-associated) variants did have smaller brains than typical mice or those with the M2145T (bipolar disorder-associated) variant.

Further, in a motor behavioral task, both K1431M and K1918X mice were less coordinated and struggled more with movement when compared with M2145T mice and typical mice. However, while the M2145T mice seemed to have no significant motor deficiency, the researchers did find a disruption in the way their neurons received and processed information.

Interestingly, there also seemed to be a difference between female and male mice when it came to social behaviors. For example, compared with their counterparts, female K1431M mice showed a heightened sign of anxiety when faced with mice they had not previously met. Meanwhile, M2145T female mice performed poorer than their male counterparts in object recognition tasks, which measure memory and learning ability.

These distinct behavioral changes had not been previously reported, and they demonstrate the importance of having in vivo models that resemble genetic variations in humans. “Without it, you might miss important things that happen in the actual organism versus in the cell lines,” says Jeng.

When neurons communicate, one cell releases chemical signals that travel over and bind to receptors on the second cell. Many studies on cellular communication focus on the receiving portion of this signal exchange, says co-first author Yevheniia Ishchenko, PhD, an associate research scientist at YSM who specializes in electrophysiology.

“But when you look at these three different variants, what differentiates them are actually deficits at the part of the neuron that releases these neurochemicals, not just the part that receives them,” she says. Ishchenko suspects that the distinct combined effects of these deficits lead to the diversity in behavioral phenotypes.

TRIO influences the activity of a signaling molecule called Rac 1, which is involved in multiple cellular events, including cytoskeletal organization and aspects of cell communication. Recent work from other scientists has shown that activity of the Rac1 signaling pathway can control the release of the neurochemical glutamate. Ishchenko found this was also true for the K1431M variant in this study. Interestingly, Rac1 activity increased in mice with K1431M variant brains; it didn’t decrease as previous biochemical studies have suggested it would. This again highlights the importance of in vivo models, Ishchenko says.

This unexpected result raised a question: Could reducing Rac1 activity restore glutamate release?

To test this, Ishchenko treated brain tissue that had the K1431M variant with a compound that inhibits Rac1. The inhibitor restored the ability of the cells to release glutamate. “That is something that in the future could translate into possible rescue or therapeutic strategy,” Ishchenko says.

The study demonstrates that studying variation in the TRIO gene in vivo could help scientists uncover what biochemical events are altered in these disorders and look for appropriate, disorder-specific interventions, Ishchenko says.

The next question is, “Can we rescue some of the behavioral changes associated with these variants by normalizing Rac1 signaling?” she asks. “We’re looking into that now.”

Research reported in this release was supported by the National Institutes of Health (award numbers T32GM136651, R56MH122449, R01MH133562, and R01MH132685) and Yale University. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Support was also provided by the American Heart Association (award 20POST35210428) and the Simons Foundation.