Chronic exposure to drugs of abuse leads to persistent changes in synaptic connectivity which underlie the complex behaviors that characterize addiction. Thus, uncovering the factors that regulate synaptic plasticity is critical for understanding the molecular underpinnings of drug-induced neural adaptation and improving our ability to treat addiction. Several studies to date have focused on epigenetic mechanisms of gene expression that regulate the genome, whereas modifications to the transcriptome have been largely overlooked. Methylation of adenosine residues (m6A) has recently been shown to be a widespread RNA modification found in thousands of cellular mRNAs. Furthermore, m6A is particularly abundant within the brain, and its regulation has been implicated in the behavioral and electrophysiological response to cocaine. Recent studies have begun to reveal that m6A regulates gene expression changes during synaptic activity. However, whether m6A contributes to synaptic changes in gene expression that underlie drug-induced plasticity remains unknown. Here, we will explore the novel hypothesis that m6A-mediated changes in local protein production at the synapse regulate gene expression changes caused by drugs of abuse. First, we will identify cocaine-induced changes to the local methylome within the mouse brain and identify potential synaptic mRNAs which are regulated through mRNA methylation. Second, we will develop novel tools for the in vivo identification of transient m6A:protein interactions to identify both new m6A binding proteins as well as dynamic m6A binding events induced by cocaine exposure. Third, we will use a combination of global gene expression profiling and gene targeting approaches to determine how m6A regulates local gene expression following cocaine exposure. Collectively, these studies will explore novel roles of the epitranscriptome in controlling drug-induced gene expression changes and will likely reveal new mechanisms that regulate long-term synaptic changes that occur during addiction.
Chronic exposure to drugs of abuse causes changes in gene expression at the synapse which are regulated through poorly understood mechanisms. This proposal will investigate the novel hypothesis that chemical modifications to synaptic mRNAs contribute to gene expression regulation during drug exposure. These experiments are likely to uncover novel pathways that are important for synaptic mRNA regulation and have the potential identify new therapeutic targets for human disease.
