# Rac-GEF signaling in dendritic spines

> **NIH NIH R01** · NORTHWESTERN UNIVERSITY · 2024 · $650,204

## Abstract

ABSTRACT
The number, size, and plasticity of spiny excitatory synapses underlies connectivity in neuronal circuits, and
their alterations are central to the pathogenesis of neurodevelopmental disorders (NDDs), including autism
spectrum disorder (ASD), intellectual disability (ID), and fragile X syndrome (FXS). Our long-term goals is
to uncover the biological functions of Rho-like small GTPase pathways at central excitatory synapses and
their contributions to NDDs. Rho GTPases, including Rac1, play key role in spiny excitatory synapse
formation, plasticity, neurotransmission, circuit development, and behavior. Conversely, alterations in Rho
GTPase signaling occur in many NDDs, including ASD, ID, and FXS. Notably, overactivation of this pathway
occurs in FXS model mice (Fmr1 KO), as well as in patients with gain-of-function mutations in the TRIO,
RAC1, and PAK1 genes, and is associated with synaptic hyperconnectivty, hyperexcitability, ASD, ID, and
epilepsy. Hence detailed knowledge of the regulation of Rho GTPases and ability to modulate them would
have broad implications for understanding brain function and dysfunction in NDDs. Rho GTPases are
directly activated by guanine-nucleotide exchange factors (GEFs). The paralog GEFs kalirin and Trio are
important regulators of neuronal connectivity, and are dysregulated in several NDDs. Both proteins directly
activate Rac1 and subsequently, p21-activated kinase (Pak), which also play key roles in brain development,
plasticity, and NDDs. Notably, inhibition of Rac1 and Pak rescued phenotypes in Fmr1 KO mice. Here we
outline a set of experiments designed to determine the role of the kalirin/Trio->Rac1->Pak axis in basal
brain function and in preclinical models of NDDs characterized by excessive synaptic connectivity
(hyperconnectivity). Specifically, we will test whether inhibition of the kalirin/Trio->Rac1->Pak axis to
reverse structural, functional, and behavioral deficits in several mouse models relevant for NDDs. We will
pursue the following Specific Aims: 1) To characterize the biological effects of kalirin/Trio inhibition in basal
brain function in mice. 2) To determine the effects of genetic deletion of kalirin and Trio on disease-relevant
phenotypes in mouse models of NDD with synaptic hyperconnectivity. 3) To compare the biological effects
of kalirin/Trio inhibition with that of known Rac1 and Pak inhibitors in mouse models of NDD with synaptic
hyperconnectivity.

## Key facts

- **NIH application ID:** 10873294
- **Project number:** 5R01MH071316-18
- **Recipient organization:** NORTHWESTERN UNIVERSITY
- **Principal Investigator:** Maria V. Barbolina
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $650,204
- **Award type:** 5
- **Project period:** 2005-06-01 → 2028-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10873294

## Citation

> US National Institutes of Health, RePORTER application 10873294, Rac-GEF signaling in dendritic spines (5R01MH071316-18). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10873294. Licensed CC0.

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