Ethanol and a rapid-acting antidepressant produce overlapping changes in exon expression in the synaptic transcriptome

Sarah A. Wolfe, Sean P. Farris, Joshua E. Mayfield, Chelcie F. Heaney, Emma K. Erickson, R. Adron Harris, R. Dayne Mayfield, Kimberly F. Raab-Graham

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

Alcohol use disorder (AUD) and major depressive disorder (MDD) are prevalent, debilitating, and highly comorbid disorders. The molecular changes that underlie their comorbidity are beginning to emerge. For example, recent evidence showed that acute ethanol exposure produces rapid antidepressant-like biochemical and behavioral responses. Both ethanol and fast-acting antidepressants block N-methyl-D-aspartate receptor (NMDAR) activity, leading to synaptic changes and long-lasting antidepressant-like behavioral effects. We used RNA sequencing to analyze changes in the synaptic transcriptome after acute treatment with ethanol or the NMDAR antagonist, Ro 25-6981. Ethanol and Ro 25-6981 induced differential, independent changes in gene expression. In contrast with gene-level expression, ethanol and Ro 25-6981 produced overlapping changes in exons, as measured by analysis of differentially expressed exons (DEEs). A prominent overlap in genes with DEEs indicated that changes in exon usage were important for both ethanol and Ro 25-6981 action. Structural modeling provided evidence that ethanol-induced exon expression in the NMDAR1 amino-terminal domain could induce conformational changes and thus alter NMDAR function. These findings suggest that the rapid antidepressant effects of ethanol and NMDAR antagonists reported previously may depend on synaptic exon usage rather than gene expression.

Original languageEnglish (US)
Pages (from-to)289-299
Number of pages11
JournalNeuropharmacology
Volume146
DOIs
StatePublished - Mar 1 2019

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Transcriptome
Antidepressive Agents
Exons
Ethanol
N-Methyl-D-Aspartate Receptors
Gene Expression
RNA Sequence Analysis
Major Depressive Disorder
Comorbidity
Alcohols
Ro 25-6981
Genes

Keywords

  • Alcohol use disorder
  • Alternative splicing
  • Differential exon usage
  • Major depressive disorder
  • Synaptic transcriptome

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

Cite this

Ethanol and a rapid-acting antidepressant produce overlapping changes in exon expression in the synaptic transcriptome. / Wolfe, Sarah A.; Farris, Sean P.; Mayfield, Joshua E.; Heaney, Chelcie F.; Erickson, Emma K.; Harris, R. Adron; Mayfield, R. Dayne; Raab-Graham, Kimberly F.

In: Neuropharmacology, Vol. 146, 01.03.2019, p. 289-299.

Research output: Contribution to journalArticle

Wolfe, Sarah A. ; Farris, Sean P. ; Mayfield, Joshua E. ; Heaney, Chelcie F. ; Erickson, Emma K. ; Harris, R. Adron ; Mayfield, R. Dayne ; Raab-Graham, Kimberly F. / Ethanol and a rapid-acting antidepressant produce overlapping changes in exon expression in the synaptic transcriptome. In: Neuropharmacology. 2019 ; Vol. 146. pp. 289-299.
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