# Disruption of TRIO signaling through PDE4A5 in neurodevelopmental disorders

> **NIH NIH F31** · YALE UNIVERSITY · 2021 · $46,036

## Abstract

Project Summary
Schizophrenia (SCZ) and autism (ASD) are highly debilitating neurodevelopmental disorders that affect millions
of people. An allelic series of heterozygous loss-of-function (LOF) or damaging variants spread throughout the
entire TRIO gene are significantly enriched in individuals with SCZ and ASD, suggesting that reduced TRIO
function causes pathology. Indeed, our lab has shown that deletion of a single TRIO allele in mouse cortical
excitatory neurons (in NEX-TRIO+/– mice) yields diverse behavioral deficits and severe defects in dendritic
structure and synaptic activity. TRIO acts downstream of cell surface receptors to control axon and dendrite
pathfinding, and synapse development. However, the signaling mechanisms compromised by TRIO variants and
how defects in these processes disrupt neuronal development remain completely unclear. Our lab identified
PDE4A5 as a new candidate TRIO signaling partner due to its reduced levels in TRIO-deficient mouse cortex
and its ability to co-immunoprecipitate with TRIO. My proposal will test the hypothesis that TRIO interacts
functionally with PDE4A5 to regulate neuron development and function in two complementary aims.
My first aim is to determine how TRIO and PDE4A5 interact functionally and how these functions are
impacted by disease-associated variants. PDE4A5 coimmunoprecipitates with TRIO, but how these proteins
interact and how these interactions impact each protein’s function is poorly understood. I will use purified
recombinant proteins to perform quantitative binding assays and determine whether PDE4A5 and TRIO interact
directly and define the minimal TRIO and PDE4A5 fragments sufficient to mediate interaction. I will engineer
disorder-associated variants that lie within the TRIO:PDE4A5 interaction interface to determine whether and how
these variants impact the Trio:PDE4A5 interaction. I will use my purified proteins and an arsenal of in vitro and
cell-based assays to measure how interactions between the TRIO and PDE4A5 impact their catalytic activities.
My second aim is to determine how TRIO:PDE4A5 interactions regulate neuronal development.
Disruption of a single TRIO allele in cultured cortical neurons yields defects in dendrite and dendritic spine
development similar to those observed in vivo. How disruption of TRIO:PDE4A5 interactions contributes to the
pathophysiology seen in TRIO deficient neurons is unclear. I will use shRNA-mediated knockdown of PDE4A5
to determine whether PDE4A5 is necessary for dendrite and dendritic spine development. I will perform
knockdown/complementation and confocal microscopy in cultured cortical neurons to determine whether and
how disruptions in TRIO:PDE4A5 interaction affects PDE4A45 localization and neuron development. I will use a
small-molecule PDE4A5 activator to test whether pharmacological manipulation of PDE4A5 can rescue deficits
in development of TRIO+/– and TRIO–/– cortical neurons in culture and in NEX-TRIO+/– and NEX-TRIO-/– mice.

## Key facts

- **NIH application ID:** 10313299
- **Project number:** 1F31MH127891-01
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Ellen Elizabeth Corcoran
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $46,036
- **Award type:** 1
- **Project period:** 2021-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10313299

## Citation

> US National Institutes of Health, RePORTER application 10313299, Disruption of TRIO signaling through PDE4A5 in neurodevelopmental disorders (1F31MH127891-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10313299. Licensed CC0.

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