Decreased GABAergic transmission is thought to play an important role in the development of alcohol dependence/withdrawal, but the specific genes responsible for adaptive changes in GABAergic transmission remain to be elucidated. In our studies to date, QTL analysis using three populations derived from the C57BL/6J and DBA/2J inbred mouse strains have identified several loci that contribute to genetic differences in acute alcohol withdrawal severity. One alcohol withdrawal locus (Alcw1) has been localized at a high level of significance (p<.000015, relative to the null hypothesis of no linkage to an approximate 10cM from the centromere that encodes the alpha1, alpha 6, gamma2 and beta 2 subunits of GABAA receptors. Another locus (Alcw2) has tentatively been mapped on chromosome 2, and in all three populations showed the strongest association with markers located 37 cM from the centromere (p<.002). Alcw2 maps near two genes encoding neuronal subtypes of glutamic acid decarboxylase (GAD), the rate-limiting enzyme in GABA synthesis, located 43cM and 9 cM from the centromere.
Aims 1 and 2 of this proposal will use DBA/2J, C57BL/6J, and BXD recombinant inbred mice to test the hypothesis that genetically determined differences in acute alcohol withdrawal severity are correlated with differences in cDNA coding sequence between parental DBA/2J and C57BL/6J alleles, RNA transcriptional differences and/or different functional properties for the protein products of identified candidate genes encoding GABAA recptor subunits and/or GAD subtypes.
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