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

机译：乙醇和速效抗抑郁药在突触转录组中外显子表达产生重叠变化

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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.
机译：饮酒障碍（AUD）和重度抑郁症（MDD）是普遍存在的，令人衰弱的高度合并症。作为其合并症基础的分子变化开始出现。例如，最近的证据表明，急性乙醇暴露会产生类似抗抑郁药的快速生化反应和行为反应。乙醇和速效抗抑郁药均会阻断N-甲基-D-天冬氨酸受体（NMDAR）的活性，从而导致突触变化和持久的抗抑郁样行为效应。我们使用RNA测序分析了乙醇或NMDAR拮抗剂Ro 25–6981急性治疗后突触转录组的变化。乙醇和Ro 25–6981诱导基因表达的差异，独立变化。与基因水平表达相反，乙醇和Ro 25–6981产生外显子重叠变化，这是通过分析差异表达外显子（DEEs）测得的。具有DEE的基因之间的显着重叠表明，外显子使用的变化对于乙醇和Ro 25–6981的作用均很重要。结构建模提供了证据，表明乙醇诱导的NMDAR1氨基末端结构域中的外显子表达可以诱导构象变化，从而改变NMDAR功能。这些发现表明，先前报道的乙醇和NMDAR拮抗剂的快速抗抑郁作用可能取决于突触外显子的使用而不是基因表达。

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