We have recently discovered that the Rho guanine nucleotide exchange factor (RhoGEF) protein Trio, along with its paralog Kalirin, is required for glutamatergic neurotransmission 9. Rac1-mediated synaptic actin regulation in particular has been implicated in ASD and has been proposed as a likely point of convergence of many known ASD risk genes 5, 6, 8. Disrupted synaptic actin modulation at glutamatergic synapses has been identified in well-established animal models of ASD, and in some cases has been identified as the underlying cause of ASD-related behavioral phenotypes in these models 5, 6, 7. Over the past 10 years, evidence has also grown suggesting a convergence on altered regulation of glutamatergic synaptic development and function in ASD 2, 3, 4. De novo mutations identified in large exome sequencing studies have identified a number of new candidate ASD-risk genes and have ultimately led to a revised model for causation 1. There is a strong genetic basis for ASD, and recent studies now establish an important role of germline de novo mutation in ASD-risk. About 40% of individuals with ASD also display some form of developmental delay while 70% display some level of intellectual disability.

Autism-spectrum disorders or ASDs are a range of neurodevelopmental disorders that are characterized by impaired social interaction, communication and restricted and repetitive behavior. It is estimated that ~ 1% of the human population has a disorder on the Autism spectrum. Together, our findings implicate both excessive and reduced Trio activity and the resulting synaptic dysfunction in ASD-related pathogenesis, and point to the Trio-Rac1 pathway at glutamatergic synapses as a possible key point of convergence of many ASD-related genes.

In accordance with pathological increases or decreases in glutamatergic neurotransmission observed in animal models of ASD, we find that these mutations result in either reduced synaptic AMPA receptor expression or enhanced glutamatergic synaptogenesis. Our study reveals that these mutations produce either hypofunctional or hyperfunctional forms of Trio in rodent neurons in vitro. Here, in humans, we discover a large cluster of ASD-related de novo mutations in Trio’s Rac1 activating domain, GEF1. Recent studies suggest that autism spectrum disorder (ASD)-related behavioral phenotypes in animal models of ASD can be produced by dysregulation of Rac1’s control of actin polymerization at glutamatergic synapses. The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac1.

Organized trio activation key