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O'Brien MA, Weston RM, Sheth NU, et al. Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice. Front Genet. 2018;9:402doi: 10.3389/fgene.2018.00402.
O'Brien, M. A., Weston, R. M., Sheth, N. U., Bradley, S., Bigbee, J., Pandey, A., Williams, R. W., Wolstenholme, J. T., & Miles, M. F. (2018). Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice. Frontiers in genetics, 9402. https://doi.org/10.3389/fgene.2018.00402
O'Brien, Megan A, et al. "Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice." Frontiers in genetics vol. 9 (2018): 402. doi: https://doi.org/10.3389/fgene.2018.00402
O'Brien MA, Weston RM, Sheth NU, Bradley S, Bigbee J, Pandey A, Williams RW, Wolstenholme JT, Miles MF. Ethanol-Induced Behavioral Sensitization Alters the Synaptic Transcriptome and Exon Utilization in DBA/2J Mice. Front Genet. 2018 Sep 24;9:402. doi: 10.3389/fgene.2018.00402. eCollection 2018. PMID: 30319688; PMCID: PMC6166094.
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Front Genet. 2018 Sep 24;9:402. doi: 10.3389/fgene.2018.00402. eCollection 2018.

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

Frontiers in genetics

Megan A O'Brien, Rory M Weston, Nihar U Sheth, Steven Bradley, John Bigbee, Ashutosh Pandey, Robert W Williams, Jennifer T Wolstenholme, Michael F Miles

Affiliations

  1. Department of Pharmacology and Toxicology, Virginia Commonwealth University, Richmond, VA, United States.
  2. VCU Alcohol Research Center, Virginia Commonwealth University, Richmond, VA, United States.
  3. Department of Anatomy and Neurobiology, Virginia Commonwealth University, Richmond, VA, United States.
  4. Department of Genetics, Genomics and Informatics, The University of Tennessee Health Science Center, Memphis, TN, United States.
  5. Department of Neurology, Virginia Commonwealth University, Richmond, VA, United States.

PMID: 30319688 PMCID: PMC6166094 DOI: 10.3389/fgene.2018.00402

Abstract

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 vs. 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: RNAseq; ethanol; exon utilization; mRNA trafficking; sensitization; synaptic

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