# Biology of synaptic GEFs and GAPs in human neurons

> **NIH NIH P50** · NORTHWESTERN UNIVERSITY · 2024 · $513,657

## Abstract

PROJECT 2 SUMMARY
The goals of Project 2 are to use iPSC-derived neuron models and cerebral organoids to investigate the
contributions of gene expression and function to human neuron axon/dendrite growth, migration, morphology,
synaptic structure and function, and brain development. We will perform studies in iPSC models that parallel the
common themes explored in the other four projects. These common Center themes include: 1) how Trio and
SynGAP function within specific cell types regulate circuit substrates (migration/morphogenesis, synapse
connectivity, neural function); 2) how specific protein domains in Trio and SynGAP regulate circuit substrates;
and 3) how small molecule targeting of GEF/GAP domains regulate circuit substrates. We will test the
hypotheses that gene dosage, functional domains, catalytic activity, and genetic variants in Trio and SynGAP
affect the ability of human neurons to undergo normal morphogenesis, synaptogenesis, and connectivity. In Aim
1, we will determine the expression and function of Trio and SynGAP in diverse neural subtypes within
developing human neurons and organoids. In Aim 2, we will determine the physiological importance of functional
domains in Trio and SynGAP in human neurons and organoids. Finally in Aim 3, we will determine the effects of
pharmacological inhibition of Trio and SynGAP in human neurons and organoids. These proposed studies will
have a broad, long-lasting impact on the field by determining the physiological importance of individual isoforms
and domains, as well as enzymatic and non-enzymatic functions of Trio and SynGAP in human neurons.
Demonstrating effects of pharmacological modulators of Trio and SynGAP will further yield a valuable toolbox
with which to study other GEF and GAP superfamily members. Findings from Project 2 will provide fundamental
information about the neurobiology of these important regulators of GTPase signaling in the brain.

## Key facts

- **NIH application ID:** 10862386
- **Project number:** 1P50MH132775-01A1
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Alfred L. George
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $513,657
- **Award type:** 1
- **Project period:** 2024-05-01 → 2029-02-28

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10862386

## Citation

> US National Institutes of Health, RePORTER application 10862386, Biology of synaptic GEFs and GAPs in human neurons (1P50MH132775-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10862386. Licensed CC0.

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