# AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $329,318

## Abstract

Epilepsy affects 3 million people in the United States. Despite the development of current antiepileptic
drugs to raise seizure threshold, one-third of epilepsy patients either respond poorly to the drugs or remain drug-
resistant. Our research aims to facilitate the understanding neuronal excitability dysregulation in epilepsy with
the intention to improve therapeutic outcome. We focus on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic
acid receptor (AMPA receptor; AMPAR), the most abundant receptor in the nervous system and one of the well-
studied excitatory synaptic proteins. Elevated levels of AMPAR have been observed in epilepsy patients, and
pharmacologically inhibiting AMPAR has been used in clinical practice for alleviating epilepsy. Despite all these
facts, it remains unclear how the homeostasis of AMPAR mediates brain excitability and how dysregulated
AMPAR contributes to epilepsy. We recently identified a novel ubiquitin E3 ligase for the GluA1 subunit of
AMPAR, neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2). Nedd4-2 is
encoded by an epilepsy-associated gene, in which three missense mutations have been identified in patients
with epilepsy. Our recent publication demonstrated that Nedd4-2 mediates neuronal and brain excitability in an
AMPAR-dependent manner (Zhu et al., PLOS Genetics, 2017). However, it remains unknown (1) whether and
how Nedd4-2 modulates AMPAR to affect excitatory synaptic transmission; and (2) how epilepsy-associated
mutations affect the functions of Nedd4-2 in this regard. Aim 1 and Aim 2 are designed to answer these questions.
Nedd4-2 is a target gene of, and transcriptionally repressed by, the tumor suppressor p53. Our work showed
that inhibition of p53 reduces acute seizure susceptibility in mice in a Nedd4-2-dependent manner. This finding,
together with our previous work, suggests p53-Nedd4-2 as a novel signaling axis to maintain brain excitability
presumably through limiting AMPAR. Aim 3 will study the regulation of p53-Nedd4-2 signaling and AMPAR
ubiquitination using a preclinical model of temporal lobe epilepsy in mice, and determine the roles of p53-Nedd4-
2 signaling in epileptogenesis in this model. Successfully accomplishing this project will improve the
understanding of ion channel dysregulation in epilepsy and foster future development of therapies in treating
epilepsy.

## Key facts

- **NIH application ID:** 10128510
- **Project number:** 5R01NS105615-04
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
- **Principal Investigator:** Nien-Pei Tsai
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $329,318
- **Award type:** 5
- **Project period:** 2018-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128510

## Citation

> US National Institutes of Health, RePORTER application 10128510, AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability (5R01NS105615-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128510. Licensed CC0.

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