Mutation of novel ethanol-responsive lncRNA Gm41261 impacts ethanol-related behavioral responses in mice.

Autor: Plasil SL; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Farris SP; Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Biomedical Informatics, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA., Blednov Y; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA., Mayfield RD; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA.; Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Mangieri RA; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA.; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA., Nwokeji UJ; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA., Aziz HC; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA.; Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, Texas, USA., Lambeth PS; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA.; Department of Neuroscience, The University of Texas at Austin, Austin, Texas, USA., Harris RA; The Waggoner Center for Alcohol and Addiction Research, The University of Texas at Austin, Austin, Texas, USA., Homanics GE; Department of Pharmacology and Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Anesthesiology and Perioperative Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.; Department of Neurobiology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA.
Jazyk: angličtina
Zdroj: Genes, brain, and behavior [Genes Brain Behav] 2024 Feb; Vol. 23 (1), pp. e12886.
DOI: 10.1111/gbb.12886
Abstrakt: Chronic alcohol exposure results in widespread dysregulation of gene expression that contributes to the pathogenesis of Alcohol Use Disorder (AUD). Long noncoding RNAs are key regulators of the transcriptome that we hypothesize coordinate alcohol-induced transcriptome dysregulation and contribute to AUD. Based on RNA-Sequencing data of human prefrontal cortex, basolateral amygdala and nucleus accumbens of AUD versus non-AUD brain, the human LINC01265 and its predicted murine homolog Gm41261 (i.e., TX2) were selected for functional interrogation. We tested the hypothesis that TX2 contributes to ethanol drinking and behavioral responses to ethanol. CRISPR/Cas9 mutagenesis was used to create a TX2 mutant mouse line in which 306 base-pairs were deleted from the locus. RNA analysis revealed that an abnormal TX2 transcript was produced at an unchanged level in mutant animals. Behaviorally, mutant mice had reduced ethanol, gaboxadol and zolpidem-induced loss of the righting response and reduced tolerance to ethanol in both sexes. In addition, a male-specific reduction in two-bottle choice every-other-day ethanol drinking was observed. Male TX2 mutants exhibited evidence of enhanced GABA release and altered GABA A receptor subunit composition in neurons of the nucleus accumbens shell. In C57BL6/J mice, TX2 within the cortex was cytoplasmic and largely present in Rbfox3+ neurons and IBA1+ microglia, but not in Olig2+ oligodendrocytes or in the majority of GFAP+ astrocytes. These data support the hypothesis that TX2 mutagenesis and dysregulation impacts ethanol drinking behavior and ethanol-induced behavioral responses in mice, likely through alterations in the GABAergic system.
(© 2024 The Authors. Genes, Brain and Behavior published by International Behavioural and Neural Genetics Society and John Wiley & Sons Ltd.)
Databáze: MEDLINE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje