# Uncovering the Role of TRIO in Synaptic Function and Autism Spectrum Disorder

> **NIH NIH R01** · UNIVERSITY OF SOUTHERN CALIFORNIA · 2021 · $360,938

## Abstract

Program Director/Principal Investigator (Last, First, Middle): Herring, Bruce, E.
PROJECT SUMMARY
Autism Spectrum Disorder (ASD) is a leading cause of mental impairment for which there is no known cure.
Mounting evidence points to a convergence on altered actin-mediated regulation of postsynaptic glutamatergic
synaptic function as a basis for ASD. We have recently identified an unprecedented clustering of ASD-related
mutations in the GEF1 domain of the synaptic actin regulatory protein, Trio, that results in a strong genome-wide
statistical association of the TRIO gene with ASD. The long-term goal of our research is to identify core synaptic
regulatory machinery onto which numerous ASD causing factors converge. Identification of synaptic
“convergence points” of ASD-risk genes will help simplify the genetic landscape of this disorder and thus, aid in
the development of new strategies to treat individuals with a diverse array of ASD-causing factors. Our central
hypothesis is that ASD mutations in Trio disrupt a multitude of synaptic regulatory pathways, and that disruption
of these pathways results in glutamatergic synapse dysfunction that contributes to the development of ASD-
related behavioral phenotypes. Guided by strong preliminary data we will pursue this hypothesis in three specific
aims. In Aim 1, we will combine proteomic, biochemical, electrophysiological, and super-resolution imaging
techniques to identify novel synaptic regulatory mechanisms involving Trio. In Aim 2, we will combine these same
approaches with computational modeling to reveal Trio-related synaptic regulatory mechanisms disrupted by
Autism-related mutations and provide a comprehensive picture of the synaptic disruption that results from
Autism-specific Trio dysfunction. And, for Aim 3, we have engineered a conditional knock-in mouse that allows
CRE-dependent expression of an ASD-related mutant form of Trio. Using this new and powerful genetic tool, we
will conduct a battery of behavioral tests to assess the impact of ASD-related Trio mutations on mammalian
behavior. Growing evidence now suggests that neurological sensory processing deficits underlie the
development of many common ASD-related behavioral phenotypes. Because of this, we propose the use of
state-of-the-art techniques that allow careful examination of somatosensory processing in these mice. The
present proposal is innovative because it assembles a team of collaborators with diverse areas of expertise and
deploys new and powerful genetic tools that will allow a multi-dimensional approach to understanding how
disruption of synaptic function leads to ASD. The proposal is significant because it stands to identify an important
synaptic signaling hub that links numerous synaptic proteins previously implicated in ASD and will vertically
advance our understanding of ASD from synapse to circuit to behavior. This proposal squarely meets the mission
objectives of the NINDS given its focus on how synaptic dysfunction ulti...

## Key facts

- **NIH application ID:** 10167804
- **Project number:** 5R01NS112480-03
- **Recipient organization:** UNIVERSITY OF SOUTHERN CALIFORNIA
- **Principal Investigator:** Bruce Herring
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $360,938
- **Award type:** 5
- **Project period:** 2019-08-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10167804

## Citation

> US National Institutes of Health, RePORTER application 10167804, Uncovering the Role of TRIO in Synaptic Function and Autism Spectrum Disorder (5R01NS112480-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10167804. Licensed CC0.

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