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

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.

Transcriptomics identifies STAT3 as a key regulator of hippocampal gene expression and anhedonia during withdrawal from chronic alcohol exposure

“…Notably, the transcriptome of postmortem hippocampus of human subjects with AUD has been analyzed and, similar to our results, changes in genes related to RNA processing and immune response pathways have been found 48 , 51 . The behavioral implications and molecular details of altered expression of RNA splicing factors have not been investigated in the context of chronic alcohol exposure and withdrawal, although Wolfe et al 52 demonstrated that the synaptic transcriptome is changed in the hippocampus of mice treated acutely with ethanol, resulting in differential exon usage. Chronic alcohol exposure and withdrawal, by changing the expression of splicing factors, could conceivably alter exon usage, leading to alterations in synaptic proteins and ultimately impacting depression-like behavior.…”

Chronic repeated predatory stress induces resistance to quinine adulteration of ethanol in male mice

“…The link between mood disorders and ethanol consumption is well studied, with the understanding that prior stress may exacerbate excessive ethanol consumption [21][22][23]. This connection may be strengthened by the antidepressant effects of ethanol, with its consumption acting as a mechanism of self-medication to mitigate the unwanted psychological effects of stress [24][25][26]. Early life and adult stress influences the development of alcohol use disorder [27][28][29][30][31], but few studies have considered the potential sex differences in these effects using preclinical models.…”

It is not just about transcription: involvement of brain RNA splicing in substance use disorders

“…In mice, acute ethanol treatment altered the exon usage of genes that significantly overlapped with changes observed in mice treated with an NMDAR antagonist, Ro 25-6981. As alcohol and Ro 25-6981 can both have rapid antidepressant effects, these results implicate alternative splicing as a potential mechanism for the behavioral effects (Wolfe et al 2019 ).…”