Abstract
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac1. 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. Here, in humans, we discover a large cluster of ASD-related de novo mutations in Trio’s Rac1 activating domain, GEF1. Our study reveals that these mutations produce either hypofunctional or hyperfunctional forms of Trio in rodent neurons in vitro. 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. 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.
Highlights
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac[1]
Disrupted synaptic actin modulation at glutamatergic synapses has been identified in well-established animal models of autism spectrum disorder (ASD), and in some cases has been identified as the underlying cause of ASD-related behavioral phenotypes in these models[5,6,7]
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]
Summary
The Rho guanine nucleotide exchange factor (RhoGEF) Trio promotes actin polymerization by directly activating the small GTPase Rac[1]. 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 degree of mutational clustering that we find in Trio’s GEF1 domain and the computationally predicted impact of these ASD-related de novo mutations on Trio-Rac[1] interactions suggest a strong association of Trio-Rac[1] pathway dysregulation in ASD-related pathologies. Systematic examination of these mutations in Trio-9 reveals both hypomorphic and hypermorphic mutations that dramatically and bidirectionally affect Trio’s function and Trio’s influence on glutamatergic neurotransmission in hippocampal CA1 pyramidal neurons. Our study uncovers ASD-related missense mutations in a single synaptic Rac1-activating protein that can produce bidirectional alterations of glutamatergic neurotransmission and implicates both reduced and excessive Trio activity and the resulting synaptic dysfunction in ASD-related disease
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