# Mechanism of Gp1 mGluR-dependent translation and plasticity

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN · 2021 · $377,746

## Abstract

PROJECT SUMMARY/ABSTRACT
 Adaptation of living organisms to constantly changing environments depends on the plasticity of the
nervous system. Neuronal plasticity often requires activity-dependent translation to rapidly supply selected
proteins, for example, through activation of Group 1 metabotropic glutamate receptors (Gp1 mGluRs). Gp1
mGluRs, including mGluR1 and mGluR5, mediate translation-dependent synaptic plasticity, including long-term
synaptic depression (LTD). Dysregulated Gp1 mGluR signaling is observed with various neurological and mental
disorders, including Fragile X Syndrome (FXS) and autism spectrum disorders (ASDs). Although
pharmacological correction of Gp1 mGluR activity reverses many of the phenotypes in animal models of those
diseases, the molecular and cellular mechanisms underlying Gp1 mGluR-mediated synaptic plasticity have been
elusive. Our published and preliminary data introduce the ubiquitin E3 ligase Murine double minute-2 (Mdm2) as
a novel translational repressor and a “switch” that permits Gp1 mGluR-induced protein translation (Liu et al.,
Hum Mol Genet., 2017). In our proposed research, we aim to characterize the role of Mdm2 in Gp1 mGluR-
dependent synaptic plasticity (Aim 1) and determine the mechanism by which Mdm2 mediates activity-dependent
protein translation (Aim 2). Our new data also show that Mdm2 is molecularly altered and unresponsive to Gp1
mGluR activation in the Fmr1 knockout (KO) mouse, the commonly used animal model for studying FXS (Tsai
et al., Hum Mol Genet., 2017). In Aim 3 we will characterize the mechanism by which Fmr1 interconnects Gp1
mGluR signaling to permit translational activation through de-repressing Mdm2. Successful completion of this
proposal will greatly facilitate the understanding of Gp1 mGluR-mediated synaptic plasticity through a novel
mechanism of translational control. Building on the deep knowledge of Mdm2 in cancer biology, our research
will also open a new avenue for the study of neurological disorders associated with abnormal Gp1 mGluR
signaling.

## Key facts

- **NIH application ID:** 10094921
- **Project number:** 1R01MH124827-01
- **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:** $377,746
- **Award type:** 1
- **Project period:** 2020-12-01 → 2025-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10094921

## Citation

> US National Institutes of Health, RePORTER application 10094921, Mechanism of Gp1 mGluR-dependent translation and plasticity (1R01MH124827-01). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10094921. Licensed CC0.

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