PLoS Genetics (Aug 2010)

Conserved role of unc-79 in ethanol responses in lightweight mutant mice.

  • David J Speca,
  • Daisuke Chihara,
  • Amir M Ashique,
  • M Scott Bowers,
  • Jonathan T Pierce-Shimomura,
  • Jungsoo Lee,
  • Nusrat Rabbee,
  • Terence P Speed,
  • Rodrigo J Gularte,
  • James Chitwood,
  • Juan F Medrano,
  • Mark Liao,
  • James M Sonner,
  • Edmond I Eger,
  • Andrew S Peterson,
  • Steven L McIntire

DOI
https://doi.org/10.1371/journal.pgen.1001057
Journal volume & issue
Vol. 6, no. 8

Abstract

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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.