Publication Details

Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice.

Authors:Kirstein SL, Davidson KL, Ehringer MA, Sikela JM, Erwin VG, Tabakoff B
Title:Quantitative trait loci affecting initial sensitivity and acute functional tolerance to ethanol-induced ataxia and brain cAMP signaling in BXD recombinant inbred mice.
Journal:The Journal of pharmacology and experimental therapeutics Sep 2002 , Vol 302 , pp. 1238-45
Abstract:In previous work, we identified genetic correlations between cAMP accumulation in the cerebellum and sensitivity to the incoordinating effects of ethanol. A genetic correlation suggests that common genes underlie the phenotypes investigated. One method for provisionally identifying genes involved in a given phenotypic measure is quantitative trait locus (QTL) analysis. Using a panel of 30 BXD recombinant inbred strains of mice and the progenitors (DBA/2J and C57BL/6J), and the dowel test for ataxia, we measured the blood ethanol concentrations at the time an animal first fell from the dowel and acute functional tolerance (AFT), and investigated cAMP signaling in the cerebellum. Cyclic AMP accumulation was measured in whole-cell preparations of cerebellar minces from individual mice under basal or stimulated conditions. We conducted a genome-wide QTL analysis of the behavioral and biochemical measures with >2000 genetic markers to identify significant associations. Western blot and comparative sequencing analysis were used to compare cAMP response element binding protein (CREB) levels and protein-coding sequence, respectively. QTL analyses correlating strain means with allelic status at genetic markers identified several significant associations (p < 0.01). Analysis of variance revealed an effect of strain on behavioral and biochemical measures. There was a significant genetic correlation between initial sensitivity and basal cAMP accumulation in the cerebellum. We identified 6 provisional QTLs for initial sensitivity on four chromosomes, 6 provisional QTLs for AFT on four chromosomes, and 11 provisional QTLs for cAMP signaling on nine chromosomes. Two loci were found to overlap for measures of initial sensitivity and for cAMP signaling. Given the genetic correlation between initial sensitivity and basal cAMP accumulation, we investigated candidate genes in a QTL on chromosome 1. Comparative sequence analysis was performed, and protein levels were compared between C57 and DBA mice for Creb1. No significant differences were detected in coding sequence or protein levels for CREB. These results suggest that although ethanol sensitivity and cAMP signaling are determined by multiple genes, they may share certain genetic codetermination.   PUBMED: 12183685
Ontological Annotations:
  • D002875: Chromosomes (Publication, NCBO Annotator)
  • D020218: Response Elements (Publication, NCBO Annotator)
  • D051379: Mice (Publication, NCBO Annotator)
  • MA:0000198: cerebellum (Publication, NCBO Annotator)
  • D008811: Mice, Inbred DBA (Publication, NCBO Annotator)
  • D017421: Sequence Analysis (Publication, NCBO Annotator)
  • D014937: Work (Publication, NCBO Annotator)
  • MA:0000059: blood (Publication, NCBO Annotator)
  • GO:0005694: chromosome (Publication, NCBO Annotator)
  • D002878: Chromosomes, Human, Pair 1 (Publication, NCBO Annotator)
  • D017362: Cyclic AMP Response Element-Binding Protein (Publication, NCBO Annotator)
  • GO:0019933: cAMP-mediated signaling (Publication, NCBO Annotator)
  • D001288: Attention (Publication, NCBO Annotator)
  • D013995: Time (Publication, NCBO Annotator)
  • D002531: Cerebellum (Publication, NCBO Annotator)
  • D000249: Adenosine Monophosphate (Publication, NCBO Annotator)
  • D000818: Animals (Publication, NCBO Annotator)
  • D015153: Blotting, Western (Publication, NCBO Annotator)
  • D001921: Brain (Publication, NCBO Annotator)
  • D002352: Carrier Proteins (Publication, NCBO Annotator)
  • D001259: Ataxia (Publication, NCBO Annotator)
  • D001769: Blood (Publication, NCBO Annotator)
  • D000704: Analysis of Variance (Publication, NCBO Annotator)
  • GO:0035497: cAMP response element binding (Publication, NCBO Annotator)
  • MA:0000168: brain (Publication, NCBO Annotator)
  • D059019: Clinical Coding (Publication, NCBO Annotator)
  • D000431: Ethanol (Publication, NCBO Annotator)
  • D001244: Association (Publication, NCBO Annotator)
  • MP:0001393: ataxia (Publication, NCBO Annotator)
  • D008815: Mice, Inbred Strains (Publication, NCBO Annotator)
  • D000242: Cyclic AMP (Publication, NCBO Annotator)
  • D040641: Quantitative Trait Loci (Publication, NCBO Annotator)
  • GO:0005488: binding (Publication, NCBO Annotator)
  • D005819: Genetic Markers (Publication, NCBO Annotator)
  • GO:0023052: signaling (Publication, NCBO Annotator)

3 GeneSets from this Publication:

Select gene sets below using the check boxes, and then add them to a project using the pull down below. You can also create a project using the pull down. To view a set, click on the GeneSetID:GeneSet Description shown in green below.
Expand Tier II Mouse 361 Genes GS135541: cerebellar cAMP 4 (Ccmp4, Published QTL Chr 4)
Expand Tier II Mouse 852 Genes GS135542: cerebellar cAMP 5 (Ccmp5, Published QTL Chr 7)
Expand Tier II Mouse 715 Genes GS135815: ethanol induced ataxia 10 (Etax10, Published QTL Chr 11)