Abstract
The mechanisms by which ethanol and inhaled anesthetics influence the nervous system are poorly understood. Here we describe the positional cloning and characterization of a new mouse mutation isolated in an N-ethyl-N-nitrosourea (ENU) forward mutagenesis screen for animals with enhanced locomotor activity. This allele, Lightweight (Lwt), disrupts the homolog of the Caenorhabditis elegans (C. elegans) unc-79 gene. While Lwt/Lwt homozygotes are perinatal lethal, Lightweight heterozygotes are dramatically hypersensitive to acute ethanol exposure. Experiments in C. elegans demonstrate a conserved hypersensitivity to ethanol in unc-79 mutants and extend this observation to the related unc-80 mutant and nca-1;nca-2 double mutants. Lightweight heterozygotes also exhibit an altered response to the anesthetic isoflurane, reminiscent of unc-79 invertebrate mutant phenotypes. Consistent with our initial mapping results, Lightweight heterozygotes are mildly hyperactive when exposed to a novel environment and are smaller than wild-type animals. In addition, Lightweight heterozygotes exhibit increased food consumption yet have a leaner body composition. Interestingly, Lightweight heterozygotes voluntarily consume more ethanol than wild-type littermates. The acute hypersensitivity to and increased voluntary consumption of ethanol observed in Lightweight heterozygous mice in combination with the observed hypersensitivity to ethanol in C. elegans unc-79, unc-80, and nca-1;nca-2 double mutants suggests a novel conserved pathway that might influence alcohol-related behaviors in humans.
Highlights
Alcohol is enjoyed by many, but its abuse can lead to enormous adverse individual and societal consequences
Studies of twins indicate that there is a substantial genetic component to this disease; it has been difficult to identify underlying genetic factors in humans, in part because of the small effect of any one gene. Because of their genetic uniformity, subtle effects on behavior of single gene deletions can be detected in inbred mice and used to model human disease
We describe the identification of a new mouse mutant, named Lightweight, with altered response to alcohol and inhaled anesthetics
Summary
Alcohol is enjoyed by many, but its abuse can lead to enormous adverse individual and societal consequences. Adoption, and family studies suggest that there is a strong genetic component to alcoholism [2,3], identifying susceptibility factors in human populations is difficult because of the heterogeneity of the disorder and the likelihood that there are multiple genes of small effect that contribute to the disease. Invertebrate genetic screens have identified several genes with clear effects on response to ethanol and inhaled anesthetics. Mutants are hypersensitive to the immobilizing effects of halothane and other anesthetic agents [4,5]. Unc-79 mutants are reported to have altered responses to the immobilizing effects of ethanol [6]. In Drosophila melanogaster (Drosophila), Krishnan and Nash identified an allele of the narrow abdomen (na) gene in a forward mutagenesis screen for halothane sensitivity [7].
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