Uncovering Trio’s role in autism spectrum disorder

  • Awarded: 2017
  • Award Type: Pilot
  • Award #: 503736

Autism spectrum disorders (ASDs) are a range of neurodevelopmental disorders characterized by impaired social interaction and communication, and restricted and repetitive behavior. It is now believed that many cases of ASD are caused by spontaneous mutations that occur in the human genome, and hundreds of genes have been now been implicated in the development of ASD. Given the large amount of diversity in the function of these genes, a critical goal now is to identify convergence points of common neuronal functions that are disrupted by these numerous ASD-related mutations. By identifying these core neuronal functions and the ASD-risk genes that directly control these functions, we stand to identify new and broadly applicable drug targets.

Growing evidence points to glutamatergic synapse dysfunction as one of these core contributors to the development of ASD. Bruce Herring’s laboratory has recently discovered a hotspot of ASD-related de novo mutations in the glutamatergic synapse regulatory protein Trio1. Herring and his team have found that these ASD-related mutations in Trio give rise to either hypo- or hyper-functional forms of the protein. When expressed in neurons, these mutations produce a diverse array of alterations in glutamatergic synapse function analogous to those seen in current animal models of ASD.

Herring’s team now proposes to use a combination of electrophysiology, super resolution microscopy and rodent behavioral analysis to precisely characterize the impact of ASD-related Trio mutations on synaptic function and behavior. The results of this proposal will shed significant light on alterations to this core synapse regulatory pathway that occur in ASD and will aid in the generation of novel therapeutic agents to treat ASD.



1.Sadybekov A., et al. Nature Communications 8, 601 (2017) PubMed
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