Glypican Gene GPC5 Participates in the Behavioral Response to Ethanol: Evidence from Humans, Mice, and Fruit Flies.
- Authors
- Joslyn, Geoff; Wolf, Fred W; Brush, Gerry; Wu, Lianqun; Schuckit, Marc; White, Raymond L
- Year
- 2011
- Journal
- G3 (Bethesda, Md.)
- PMID
- 22384374
- DOI
- 10.1534/g3.111.000976
- PMCID
- PMC3276178
Alcohol use disorders are influenced by many interacting genetic and environmental factors. Highlighting this complexity is the observation that large genome-wide association experiments have implicated many genes with weak statistical support. Experimental model systems, cell culture and animal, have identified many genes and pathways involved in ethanol response, but their applicability to the development of alcohol use disorders in humans is undetermined. To overcome the limitations of any single experimental system, the analytical strategy used here was to identify genes that exert common phenotypic effects across multiple experimental systems. Specifically, we (1) performed a mouse linkage analysis to identify quantitative trait loci that influence ethanol-induced ataxia; (2) performed a human genetic association analysis of the mouse-identified loci against ethanol-induced body sway, a phenotype that is not only comparable to the mouse ethanol-ataxia phenotype but is also a genetically influenced endophenotype of alcohol use disorders; (3) performed behavioral genetic experiments in Drosophila showing that fly homologs of GPC5, the member of the glypican gene family implicated by both the human and mouse genetic analyses, influence the fly's response to ethanol; and (4) discovered data from the literature demonstrating that the genetically implicated gene's expression is not only temporally and spatially consistent with involvement in ethanol-induced behaviors but is also modulated by ethanol. The convergence of these data provides strong support to the hypothesis that GPC5 is involved in cellular and organismal ethanol response and the etiology of alcohol use disorders in humans.
Flowchart of the experimental strategy leading to the identification of GPC5 as a participant in ethanol-induced behaviors.
Drosophila glypican homologs regulate behavioral responses to acute and repeated ethanol exposure. (A) Simplified diagram of the dlp locus. Coding regions are indicated with shaded boxes. The transposon insertion allele dlpf03537 is located in the first intron. Probes for qPCR span the last intron. (B) Ethanol-stimulated locomotion of flies homozygous (left) or heterozygous (right) for f03537 continuously exposed to 47% ethanol vapor (0–25 min, bar on horizontal axis). Control in all experiments was the genetic background strain. Statistical significance (two-sample t-test) was assessed by comparison of the total distance traveled during the hyperactive phase (2–25 min). f03537: n = 5, f03537/+: n = 8. (C) Exposure scheme for inducing and detecting ethanol rapid tolerance. Flies were exposed twice to 67% ethanol vapor with 4 hr between the start of exposures 1 and 2. (D) Sedation sensitivity and tolerance of flies heterozygous for f03537. ST50 is the time to 50% sedation, and sedation tolerance is the difference between the ST50 of exposure 2 (e2) and 1 (e1). Sensitivity and sedation are illustrated by the horizontal bar graphs. *P = 0.0206, **P = 0.0022, two-sample t-test. n = 9. (E) Simplified diagram of the dally locus. (F) Ethanol-stimulated locomotion of flies homozygous (left) or heterozygous (right) for MB950 continuously exposed to 47% ethanol vapor (0–25 min). MB950: n = 7, MB950/+: n = 11. (G) Sedation sensitivity and tolerance of flies homozygous for MB950. ***P = 0.0002, two-sample t-test. n = 7. Ethanol absorption was unaltered in dlp (control: 24.6 mM, f03537/+: 24.2 mM, P = 0.8726, two-sample t-test, n = 6) and dally mutant flies (control: 29.5 mM, MB950: 31.7 mM, P = 0.5231, two-sample t-test, n = 4).
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