# RNA methylation in synaptic plasticity and drug-seeking

> **NIH NIH R01** · UNIVERSITY OF CHICAGO · 2020 · $526,060

## Abstract

Abstract
 Aberrant synaptic plasticity is a key underlying biological mechanism of drug addiction. The long-lasting
synaptic changes are dependent on changes in gene expression and evidence support the involvement of
epigenetic mechanisms. However, histone modifications, DNA methylation or DNA hydroxymethylation affects
gene expression at transcriptional level, which is not only slow in affecting protein synthesis but also lacks
synaptic specificity. RNA N6-methyladenosine (m6A) modification has been found to significantly affect RNA
splicing, export, localization, translation efficiency and stability. All there are key factors in regulating translation
and potentially localized translation in synapses. Both our preliminary data and published studies suggest that
deficiency in m6A dependent pathways significantly impairs neuronal function including dopamine signaling
and dopamine dependent learning. Therefore we propose to focus on the role of m6A modification of mRNAs in
synaptic plasticity and in drug addiction models. We will use mice with the m6A methyltransferase METTL14
deleted in D1 positive striatal neurons in the nucleus accumbens. In Aim 1, we will test the hypothesis that
mutant mice have impaired appetitive Pavlovian learning and impaired cue-induced reinstatement of cocaine
self-administration. In Aim 2, we will record from brain slices and test if mutant mice have impaired
corticostriatal plasticity and diminished changes in corticostriatal synaptic strengths caused by cocaine
exposure. In Aim 3, we will determine how m6A RNA methylation regulates synaptic protein translation in
responses to drug challenges and other changes on neuronal activity. We will first examine if cocaine exposure
in vivo affects level of m6A RNA methylation and identify downstream targets. The rest of the proposed
experiments will examine the degree to which m6A RNA methylation affects protein translation in the soma vs.
dendrites where local translation is under control of synapses. We will use dissociated neuronal cortical-striatal
co-cultures from METTL14 knockout and control mice.

## Key facts

- **NIH application ID:** 9928909
- **Project number:** 5R01DA043361-04
- **Recipient organization:** UNIVERSITY OF CHICAGO
- **Principal Investigator:** Xiaoxi Zhuang
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $526,060
- **Award type:** 5
- **Project period:** 2017-09-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9928909

## Citation

> US National Institutes of Health, RePORTER application 9928909, RNA methylation in synaptic plasticity and drug-seeking (5R01DA043361-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9928909. Licensed CC0.

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