miRNA-regulated transcription associated with mouse strains predisposed to hypnotic effects of ethanol

Studying innate sensitivity to ethanol can be an important first step toward understanding alcohol use disorders. In brain, we investigated transcripts, with evidence of miRNA modulation related to a predisposition to the hypnotic effect of ethanol, as measured by loss of righting reflex (LORR).

Expression of miRNAs (12 samples) and expression of mRNAs (353 samples) in brain were independently analyzed for an association with LORR in mice from the LXS recombinant inbred panel gathered across several small studies. These results were then integrated via a meta-analysis of miRNA-mRNA target pairs identified in miRNA-target interaction databases.

We found 112 significant miRNA-mRNA pairs where a large majority of miRNAs and mRNAs were highly interconnected. Most pairs indicated a pattern of increased levels of miRNAs and reduced levels of mRNAs being associated with more alcohol-sensitive strains. For example, CaMKIIn1 was targeted by multiple miRNAs associated with LORR. CAMK2N1 is an inhibitor of CAMK2, which among other functions, phosphorylates, or binds to GABA_A and NMDA receptors.

Our results suggest a novel role of miRNA-mediated regulation of an inhibitor of CAMK2 and its downstream targets including the GABA_A and NMDA receptors, which have been previously implicated to have a role in ethanol-induced sedation and sensitivity.