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Ethanol and a rapid-acting antidepressant produce overlapping changes in exon expression in the synaptic
Sarah A Wolfe1, Sean P Farris2, Joshua E Mayfield3
1Committee on the Neurobiology of Addictive Disorders, The Scripps Research Institute, La Jolla, CA, 92037, United States.
Neuropharmacology
|November 13, 2018
Summary
Acute ethanol and N-methyl-D-aspartate receptor (NMDAR) antagonists share rapid antidepressant effects by altering synaptic exon usage, not just gene expression. This impacts NMDAR function and offers new insights into treating alcohol and major depressive disorders.
Area of Science:
- Neuroscience
- Molecular Biology
- Pharmacology
Background:
- Alcohol use disorder (AUD) and major depressive disorder (MDD) frequently co-occur, suggesting shared underlying molecular mechanisms.
- Acute ethanol exposure exhibits rapid antidepressant-like effects, similar to N-methyl-D-aspartate receptor (NMDAR) antagonists.
- Both ethanol and NMDAR antagonists modulate synaptic function and produce long-lasting behavioral changes.
Purpose of the Study:
- To investigate the molecular changes in the synaptic transcriptome following acute ethanol or NMDAR antagonist (Ro 25-6981) treatment.
- To compare gene-level expression changes with changes in exon usage.
- To elucidate the role of exon usage in the rapid antidepressant effects of ethanol and NMDAR antagonists.
Main Methods:
- RNA sequencing was employed to analyze synaptic transcriptome alterations.
- Differential gene expression analysis was performed.
- Analysis of differentially expressed exons (DEEs) was conducted to assess changes in exon usage.
- Structural modeling was used to evaluate the functional impact of ethanol-induced exon expression.
Main Results:
- Ethanol and Ro 25-6981 induced distinct gene expression profiles.
- Overlapping changes in exon usage were observed between ethanol and Ro 25-6981 treatments, particularly in genes associated with NMDAR function.
- Structural modeling suggested that ethanol-induced changes in NMDAR1 exon expression could alter receptor conformation and function.
- Synaptic exon usage, rather than overall gene expression, appears crucial for the rapid antidepressant effects.
Conclusions:
- The rapid antidepressant effects of ethanol and NMDAR antagonists may be mediated by alterations in synaptic exon usage.
- Changes in exon expression, particularly within NMDAR subunits, play a significant role in modulating NMDAR function.
- This research highlights the importance of alternative splicing in the neurobiological effects of ethanol and antidepressants.
Keywords:
Alcohol use disorderAlternative splicingDifferential exon usageMajor depressive disorderSynaptic transcriptomeMore Related Videos
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