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

B. Vestal, P. Russell, R. A. Radcliffe, L. Bemis, L. M. Saba, K. Kechris

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Introduction: 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). Methods: 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. Results: 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. Conclusions: 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.

Original languageEnglish (US)
Article numbere00989
JournalBrain and Behavior
Volume8
Issue number6
DOIs
StatePublished - Jun 2018

Bibliographical note

Funding Information:
This work was supported in part by National Institutes of Health/NIAAA R01AA021131 (KK), R01AA016957 (RR), and R24AA013162 (BT). We thank Boris Tabakoff and Paula Hoffman for feedback on the Discussion and critically reviewing the manuscript, Yinni Yu and Adam Chapman for expert technical assistance with the microarray experiments, Colin Larson for assistance in generating the saline-treated mice data set, and the University of Colorado Denver Genomics and Microarray Core for assistance with the small RNA sequencing. All miRNA sequencing data is available on the PhenoGen website. Sequencing data for the na?ve mice only are also available on GEO (ID: GSE85389).

Funding Information:
This work was supported in part by National Institutes of Health/ NIAAA R01AA021131 (KK), R01AA016957 (RR), and R24AA013162 (BT). We thank Boris Tabakoff and Paula Hoffman for feedback on the Discussion and critically reviewing the manuscript, Yinni Yu and Adam Chapman for expert technical assistance with the mi-croarray experiments, Colin Larson for assistance in generating the saline-treated mice data set, and the University of Colorado Denver Genomics and Microarray Core for assistance with the small RNA sequencing. All miRNA sequencing data is available on the PhenoGen website. Sequencing data for the naïve mice only are also available on GEO (ID: GSE85389).

Publisher Copyright:
© 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

Keywords

  • RNA sequencing
  • calcium/calmodulin-dependent protein kinase II inhibitor 1
  • ethanol sensitivity
  • loss of righting reflex
  • mRNA expression
  • microRNA expression
  • microRNA target interactions
  • mmu-miR-106b
  • mouse brain
  • recombinant Inbred mouse strains

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