AUTHOR=Kozell Laura B. , Denmark Deaunne L. , Walter Nicole A. R. , Buck Kari J. 

TITLE=Distinct Roles for Two Chromosome 1 Loci in Ethanol Withdrawal, Consumption, and Conditioned Place Preference

JOURNAL=Frontiers in Genetics

VOLUME=9

YEAR=2018

URL=https://www.frontiersin.org/journals/genetics/articles/10.3389/fgene.2018.00323

DOI=10.3389/fgene.2018.00323

ISSN=1664-8021

ABSTRACT=<p>We previously identified a region on chromosome 1 that harbor quantitative trait loci (QTLs) with large effects on alcohol withdrawal risk using both chronic and acute models in mice. Here, using newly created and existing QTL interval-specific congenic (ISC) models, we report the first evidence that this region harbors two distinct alcohol withdrawal QTLs (<italic>Alcw1</italic><sub>1</sub>and <italic>Alcw1</italic><sub>2</sub>), which underlie 13% and 3–6%, respectively, of the genetic variance in alcohol withdrawal severity measured using the handling-induced convulsion. Our results also precisely localize <italic>Alcw1</italic><sub>1</sub> and <italic>Alcw1</italic><sub>2</sub> to discreet chromosome regions (syntenic with human 1q23.1–23.3) that encompass a limited number of genes with validated genotype-dependent transcript expression and/or non-synonymous sequence variation that may underlie QTL phenotypic effects. ISC analyses also implicate <italic>Alcw1</italic><sub>1</sub>and <italic>Alcw1</italic><sub>2</sub> in withdrawal-induced anxiety-like behavior, representing the first evidence for their broader roles in alcohol withdrawal beyond convulsions; but detect no evidence for <italic>Alcw1</italic><sub>2</sub> involvement in ethanol conditioned place preference (CPP) or consumption. Our data point to high-quality candidates for <italic>Alcw1</italic><sub>2</sub>, including genes involved in mitochondrial respiration, spatial buffering, and neural plasticity, and to <italic>Kcnj9</italic> as a high-quality candidate for <italic>Alcw1</italic><sub>1</sub>. Our studies are the first to show, using two null mutant models on different genetic backgrounds, that <italic>Kcnj9</italic><sup>−/−</sup> mice demonstrate significantly less severe alcohol withdrawal than wildtype littermates using acute and repeated exposure paradigms. We also demonstrate that <italic>Kcnj9</italic><sup>−/−</sup> voluntarily consume significantly more alcohol (20%, two-bottle choice) than wildtype littermates. Taken together with evidence implicating <italic>Kcnj9</italic> in ethanol CPP, our results support a broad role for this locus in ethanol reward and withdrawal phenotypes. In summary, our results demonstrate two distinct chromosome 1 QTLs that significantly affect risk for ethanol withdrawal, and point to their distinct unique roles in alcohol reward phenotypes.</p>