The Impact of TRIO Gene Variants on Neurodevelopmental Disorders

Researchers have uncovered how variations in the TRIO gene influence brain development and lead to a range of neurodevelopmental disorders. Their recent study, published in eLife, delves into the mechanisms behind these genetic effects, paving the way for targeted therapies.

The TRIO gene encodes a set of proteins crucial for regulating the cytoskeleton—the internal framework of cells that supports their shape and structure. Variants in this gene, especially those causing damage, have been linked with conditions such as intellectual disability, autism spectrum disorder (ASD), schizophrenia, and bipolar disorder. Despite these associations, the precise biological pathways remained elusive.

Anthony Koleske, Ph.D., a senior author from Yale School of Medicine, highlighted the significance of these findings by emphasizing that different mutations within a single gene can generate markedly diverse effects on brain growth and function. To investigate further, Koleske's team studied how three specific TRIO variants—K1431M (associated with autism), K1918X (linked to schizophrenia), and M2145T (found in bipolar disorder)—affected mice.

The researchers bred mice carrying these variants to examine their brain sizes, behavior, and neuronal activity. Notably, mice with the K1431M and K1918X mutations exhibited smaller brains, similar to human cases, whereas the M2145T variant did not significantly alter brain size. Behaviorally, mice with K1431M and K1918X showed impaired movement and coordination, while M2145T mice displayed neuron communication issues despite normal motor skills.

Interestingly, gender differences emerged. Female K1431M mice exhibited increased anxiety, while female M2145T mice performed worse in memory tests than males, highlighting sex-specific effects of these mutations. These findings underscore the importance of in vivo models in capturing the complexity of genetic influences on brain development and behavior.

At the cellular level, the study explored how TRIO variants affect neuron communication. TRIO influences Rac1, a signaling molecule involved in cell structure and communication. For example, in mice with the K1431M variant, Rac1 activity unexpectedly increased, contrary to previous biochemical studies suggesting it would decrease. This prompted testing whether inhibiting Rac1 could restore normal neuron function.

Treatment with a Rac1 inhibitor successfully rescued glutamate release—the chemical messenger neurons use to communicate—indicating potential therapeutic avenues. Such insights deepen understanding of how genetic variations disrupt biochemical pathways, leading to neurodevelopmental disorders, and open the possibility of targeted interventions.

The research exemplifies the value of studying gene variants in living organisms to uncover disease mechanisms and develop precise treatments. Ongoing investigations aim to determine if normalizing Rac1 activity can reverse behavioral abnormalities associated with these genetic mutations.

This study was led by Yevheniia Ishchenko and colleagues, with support from Yale School of Medicine, and adds important knowledge to the genetics of neurodevelopmental disorders.

Source: MedicalXpress