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Genomic and Epigenomic of Alcoholism

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Genet. | doi: 10.3389/fgene.2018.00402

Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice

Megan A. O'Brien1,  Rory M. Weston1, Nihar Sheth1, Steven Bradley1, John Bigbee1, Ashutosh Pandey2,  Robert W. Williams2,  Jennifer T. Wolstenholme1 and  Michael F. Miles1*
  • 1Pharmacology and Toxicology, Virginia Commonwealth University, United States
  • 2University of Tennessee Health Science Center, United States

Alcoholism is a complex behavioral disorder characterized by loss of control in limiting intake, and progressive compulsion to seek and consume ethanol. Prior studies have suggested that the characteristic behaviors associated with escalation of drug use are caused, at least in part, by ethanol-evoked changes in gene expression affecting synaptic plasticity. Implicit in this hypothesis is a dependence on new protein synthesis and remodeling at the synapse. It is well established that mRNA can be transported to distal dendritic processes, where it can undergo localized translation. It is unknown whether such modulation of the synaptic transcriptome might contribute to ethanol-induced synaptic plasticity. Using ethanol-induced behavioral sensitization as a model of neuroplasticity, we investigated whether repeated exposure to ethanol altered the synaptic transcriptome, contributing to mechanisms underlying subsequent increases in ethanol-evoked locomotor activity. RNAseq profiling of DBA/2J mice subjected to acute ethanol or ethanol-induced behavioral sensitization was performed on frontal pole synaptoneurosomes to enrich for synaptic mRNA. Genomic profiling showed distinct functional classes of mRNA enriched in the synaptic versus cytosolic fractions, consistent with their role in synaptic function. Ethanol sensitization regulated more than twice the number of synaptic localized genes compared to acute ethanol exposure. Synaptic biological processes selectively perturbed by ethanol sensitization included protein folding and modification as well as and mitochondrial respiratory function, suggesting repeated ethanol exposure alters synaptic energy production and the processing of newly translated proteins. Additionally, marked differential exon usage followed ethanol sensitization in both synaptic and non-synaptic cellular fractions, with little to no perturbation following acute ethanol exposure. Altered synaptic exon usage following ethanol sensitization strongly affected genes related to RNA processing and stability, translational regulation, and synaptic function. These genes were also enriched for targets of the FMRP RNA-binding protein and contained consensus sequence motifs related to other known RNA binding proteins, suggesting that ethanol sensitization altered selective mRNA trafficking mechanisms. This study provides a foundation for investigating the role of ethanol in modifying the synaptic transcriptome and inducing changes in synaptic plasticity.

Keywords: plasticity, Dendrite, Synaptoneurosome, DBA/2J, Mouse, synaptic, mRNA trafficking, RNAseq, exon utilization, Ethanol, sensitization, Alcohol use disorder (AUD)

Received: 06 Jul 2018; Accepted: 03 Sep 2018.

Edited by:

Kristin Hamre, University of Tennessee Health Science Center, United States

Reviewed by:

Minati Singh, University of Iowa, United States
Owen M. Rennert, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), United States  

Copyright: © 2018 O'Brien, Weston, Sheth, Bradley, Bigbee, Pandey, Williams, Wolstenholme and Miles. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Michael F. Miles, Virginia Commonwealth University, Pharmacology and Toxicology, Richmond, United States,