Screening for ENU-induced mutations in mice that result in aberrant ethanol-related phenotypes

Department of Psychology, The University of Memphis, Memphis, Tennessee, United States
Behavioral Neuroscience (Impact Factor: 2.73). 09/2007; 121(4):665-78. DOI: 10.1037/0735-7044.121.4.665
Source: PubMed


One way to investigate the genetic underpinnings of ethanol-related phenotypes is to create random mutations and screen the mutagenized mice for their behavioral phenotypes. The purposes of this article are to assess the efficacy of a novel high throughput screen to detect known strain differences and to provide evidence of the ability of this screen to detect phenodeviants, as illustrated by two new lines of mutant mice. All mice were tested for the following phenotypes after a dose of 2.25 g/kg of ethanol: ataxia, anxiolytic response, locomotor activity, core body temperature, and blood ethanol concentration, as well as ethanol consumption based on a two-bottle choice test. The authors obtained several baseline measures that allowed for the detection of phenodeviants on these measures as well. To validate this screen, A/J, DBA/2J, and C57BL/6J mouse strains were tested, and previously reported strain differences were found in all phenotypes except ethanol-induced hypothermia. Additionally, two mutant pedigrees were identified: 7TNJ, which exhibited abnormal ethanol-induced locomotor activity, and 112TNR, which exhibited an enhanced ability on the rotarod. These data demonstrate the efficacy of this screen to detect known as well as novel phenotypic differences.

9 Reads
  • Source
    • "In the field of alcohol research, it is apparent that complex genetic and environmental factors contribute of the effects of ethanol, and a variety of animal models have been created, using targeted and random genetic alterations and selective breeding, to examine and understand these effects (e.g., Crabbe and Belknap, 1993; Phillips, 1993; Gorwood et al., 2002; Bergstrom et al., 2003; Hoplight et al., 2007; Bell et al., 2008). Recently, the Integrative Neuroscience Initiative on Alcoholism and Tennesse Mouse Genome Consortia used ENU-mutagenesis to induce random single base-pair mutations in mice and then characterized ethanol-related phenotypes in mutated mouse lines using high-throughput behavioral screens (Kermany et al., 2006; Hamre et al., 2007). In behavioral assays described by Hamre et al (2007), the 22-TNJ mutant mouse strain was noted because it exhibited a hyperactive locomotor response to ethanol compared to 1-TNH controls. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Characterization of neurochemical and behavioral responses to ethanol in phenotypically distinct mouse strains can provide insight into the mechanisms of ethanol stimulant actions. Increases in striatal dopamine (DA) levels have often been linked to ethanol-induced hyperactivity. We examined the functional status of the DA system and behavioral responsiveness to ethanol, cocaine, and a DA-receptor agonist in an N-ethyl-N-nitrosourea-mutagenized mouse strain, 22-TNJ, generated by the Integrative Neuroscience Initiative on Alcoholism Consortium. The 22-TNJ mouse strain exhibited greater locomotor responses to 2.25g/kg ethanol and 10mg/kg cocaine, compared with control mice. In vivo microdialysis showed low-baseline DA levels and a larger DA increase with both 2.25g/kg ethanol and 10mg/kg cocaine. In in vitro voltammetry studies, the 22-TNJ mice displayed increased V(max) rates for DA uptake, possibly contributing to the low-baseline DA levels found with microdialysis. Finally, 22-TNJ mice showed enhanced in vitro autoreceptor sensitivity to the D2/D3 agonist, quinpirole, and greater locomotor responses to both autoreceptor-selective and postsynaptic receptor-selective doses of apomorphine compared with controls. Taken together, these results indicate that the dopaminergic system of the 22-TNJ mouse is low functioning compared with control, with consequent receptor supersensitivity, such that mutant animals exhibit enhanced behavioral responses to DA-activating drugs, such as ethanol. Thus, the 22-TNJ mouse represents a model for a relatively hypodopaminergic system, and could provide important insights into the mechanisms of hyper-responsiveness to ethanol's stimulant actions.
    Alcohol (Fayetteville, N.Y.) 09/2009; 43(6):421-31. DOI:10.1016/j.alcohol.2009.04.006 · 2.01 Impact Factor
  • Source
    • "Since the initial review, 34 additional papers have appeared, adding information about alcohol responses for several previously targeted genes, but also introducing 14 new genes to the mix. Two studies used ENU mutagenesis to generate novel mutants, some of which were found to differ in alcohol responses (Pawlak et al. 2005; Hamre et al. 2007). In one study, cerebellar tissue from ethanol-treated mice with or without a protein kinase C (PKC) gamma null mutation was compared in a gene expression profiling analysis. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Neurogenetic studies of alcohol dependence have relied substantially on genetic animal models, particularly rodents. Studies of inbred strains, selectively bred lines and mutants bearing genes whose function has been targeted for over or under expression are reviewed. Studies focused on gene expression changes are the most recent contributors to this literature, and some genetic effects may work through epigenetic mechanisms. In a few instances, interesting parallels have been revealed between genetic risk in humans and studies in non-human animal models. Future approaches are likely to be increasingly complex.
    Philosophical Transactions of The Royal Society B Biological Sciences 10/2008; 363(1507):3201-11. DOI:10.1098/rstb.2008.0101 · 7.06 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: A method is proposed in this paper for on line estimation of the ARMA model parameters of a system, whose input is white unmeasurable, stationary, or non-stationary noise. The method is based on the instrumental variable principle for recursive parameter estimation and on fixed-lag smoothing of the equivalent state -space model for deconvolution. The consistency and asymptotic behaviour of this approach are discussed and a simulation study is given, which supports the theoretical results.
    Decision and Control, 1984. The 23rd IEEE Conference on; 01/1985
Show more

Preview (2 Sources)

9 Reads
Available from