# Study of PAK3 in epilepsy-associated defects in synaptic plasticity

> **NIH NIH R03** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2020 · $145,533

## Abstract

PROJECT SUMMARY/ABSTRACT
 Epilepsy affects more than 3 million people in the United States. In addition to unprovoked seizures,
cognitive decline and memory impairment are common comorbidities associated with epilepsy, but our
knowledge in this area is limited. Our preliminary work suggests that an epilepsy associated ubiquitin E3
ligase Nedd4-2 mediates actin polymerization through promoting phosphorylation of an actin binding protein
cofilin during the induction of long-term synaptic potentiation (LTP). LTP describes long‐lasting increments of
synaptic efficiency and is crucial for cognition and memory formation. In an effort to identify ubiquitination
substrates of Nedd4-2 responsible for cofilin phosphorylation, we identified PAK3, an IDG-eligible understudied
kinase, as a potential substrate of Nedd4-2 that contributes to cofilin phosphorylation during LTP. This pilot
project is formulated to test our hypothesis that induction of LTP de-represses Nedd4-2 to stabilize PAK3 and
subsequently induce cofilin phosphorylation and actin polymerization. In Aim 1, we will determine how PAK3 is
ubiquitinated by Nedd4-2 and how this ubiquitination is disrupted by epilepsy associated mutations in Nedd4-2.
We will also determine whether induction of LTP de-represses Nedd4-2 to allow PAK3 stabilization during LTP.
In Aim 2, we will employ a recently developed optogenetic approach to rapidly stabilize PAK3 in Nedd4-2
conditional knockout (cKO) neurons during the induction of LTP, with the intention to restore cofilin
phosphorylation and actin polymerization, and ultimately to restore LTP. We expect our project to further our
knowledge of an IDG-eligible protein PAK3 in synaptic plasticity and help explain cognitive decline in epilepsy.

## Key facts

- **NIH application ID:** 10046413
- **Project number:** 1R03NS120516-01
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Nien-Pei Tsai
- **Activity code:** R03 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $145,533
- **Award type:** 1
- **Project period:** 2020-08-01 → 2022-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10046413

## Citation

> US National Institutes of Health, RePORTER application 10046413, Study of PAK3 in epilepsy-associated defects in synaptic plasticity (1R03NS120516-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10046413. Licensed CC0.

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