Department of Neurology and the Ernest Gallo Clinic and Research Center, University of California San Francisco, Emeryville, California, United States of America.
PLoS Genet. 2010 Aug 12;6(8):e1001057. doi: 10.1371/journal.pgen.1001057.
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.
乙醇和吸入麻醉剂影响神经系统的机制尚未完全阐明。在这里，我们描述了一种新的小鼠突变的定位克隆和特征，该突变是在增强运动活性动物的 N-乙基-N-亚硝脲（ENU）正向诱变筛选中分离出来的。这个等位基因名为 Lightweight（Lwt），它破坏了秀丽隐杆线虫（C. elegans） unc-79 基因的同源物。虽然 Lwt/Lwt 纯合子在围产期是致死的，但 Lwt 杂合子对急性乙醇暴露的敏感性显著增加。在秀丽隐杆线虫中的实验表明，unc-79 突变体对乙醇存在保守的敏感性，并将这一观察结果扩展到相关的 unc-80 突变体和 nca-1;nca-2 双突变体。Lightweight 杂合子对麻醉剂异氟烷也表现出改变的反应，类似于 unc-79 无脊椎动物突变体表型。与我们最初的定位结果一致，Lightweight 杂合子在暴露于新环境时表现出轻度多动，并且比野生型动物小。此外，Lightweight 杂合子表现出增加的食物消耗，但身体成分更瘦。有趣的是，Lightweight 杂合子自愿消耗比野生型同窝仔更多的乙醇。Lightweight 杂合子中观察到的急性乙醇超敏性和增加的自愿乙醇消耗，以及在 C. elegans unc-79、unc-80 和 nca-1;nca-2 双突变体中观察到的对乙醇的敏感性增加，表明可能影响人类与酒精相关行为的一种新的保守途径。
