title: Synaptic microRNAs Coordinately Regulate Synaptic mRNAs: Perturbation by Chronic Alcohol Consumption.
abstract: Local translation of mRNAs in the synapse has a major role in synaptic structure and function. Chronic alcohol use causes persistent changes in synaptic mRNA expression, possibly mediated by microRNAs localized in the synapse. We profiled the transcriptome of synaptoneurosomes (SN) obtained from the amygdala of mice that consumed 20% ethanol (alcohol) in a 30-day continuous two-bottle choice test to identify the microRNAs that target alcohol-induced mRNAs. SN are membrane vesicles containing pre- and post-synaptic compartments of neurons and astroglia and are a unique model for studying the synaptic transcriptome. We previously showed that chronic alcohol regulates mRNA expression in a coordinated manner. Here, we examine microRNAs and mRNAs from the same samples to define alcohol-responsive synaptic microRNAs and their predicted interactions with targeted mRNAs. The aim of the study was to identify the microRNA-mRNA synaptic interactions that are altered by alcohol. This was accomplished by comparing the effect of alcohol in SN and total homogenate preparations from the same samples. We used a combination of unbiased bioinformatic methods (differential expression, correlation, co-expression, microRNA-mRNA target prediction, co-targeting, and cell type-specific analyses) to identify key alcohol-sensitive microRNAs. Prediction analysis showed that a subset of alcohol-responsive microRNAs was predicted to target many alcohol-responsive mRNAs, providing a bidirectional analysis for identifying microRNA-mRNA interactions. We found microRNAs and mRNAs with overlapping patterns of expression that correlated with alcohol consumption. Cell type-specific analysis revealed that a significant number of alcohol-responsive mRNAs and microRNAs were unique to glutamate neurons and were predicted to target each other. Chronic alcohol consumption appears to perturb the coordinated microRNA regulation of mRNAs in SN, a mechanism that may explain the aberrations in synaptic plasticity affecting the alcoholic brain.
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.|Institute for Neuroscience (INS), University of Texas at Austin, Austin, TX, USA.
authors.forename: Dana
authors.identifier: http://orcid.org/0000-0002-6262-077X
authors.initials: D
authors.lastname: Most
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: Courtney
authors.initials: C
authors.lastname: Leiter
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: Yuri A
authors.initials: YA
authors.lastname: Blednov
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: R Adron
authors.initials: RA
authors.lastname: Harris
authors.affiliation: Waggoner Center for Alcohol and Addiction Research, University of Texas at Austin, Austin, TX, USA.
authors.forename: R Dayne
authors.initials: RD
authors.lastname: Mayfield
mesh_terms: D000428:Alcohol Drinking / Q000378:metabolism*; D019973:Alcohol-Related Disorders / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism*; D002492:Central Nervous System Depressants / Q000633:toxicity; D002755:Choice Behavior / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D000431:Ethanol / Q000633:toxicity; D005260:Female; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000378:metabolism*; D046228:Microarray Analysis; D012333:RNA, Messenger / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D013569:Synapses / Q000187:drug effects / Q000378:metabolism*; D059467:Transcriptome / Q000187:drug effects / Q000502:physiology
chemical_list: D002492:Central Nervous System Depressants; D035683:MicroRNAs; D012333:RNA, Messenger; D000431:Ethanol