The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans

• Verfasst von: Gonzalez, Dante [VerfasserIn]
• Verfasst von: Banaschewski, Tobias [VerfasserIn]
• Verfasst von: Flor, Herta [VerfasserIn]
• Titel: The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans
• Verf.angabe: Dante A. Gonzalez, Tianye Jia, Jorge H. Pinzón, Summer F. Acevedo, Shamsideen A. Ojelade, Bing Xu, Nicole Tay, Sylvane Desrivières, Jeannie L. Hernandez, Tobias Banaschewski, Christian Büchel, Arun L.W. Bokde, Patricia J. Conrod, Herta Flor, Vincent Frouin, Jürgen Gallinat, Hugh Garavan, Penny A. Gowland, Andreas Heinz, Bernd Ittermann, Mark Lathrop, Jean-Luc Martinot, Tomás Paus, Michael N. Smolka, Aylin R. Rodan, Gunter Schumann, and Adrian Rothenfluh
• Jahr: 2018
• Jahr des Originals: 2017
• Umfang: 8 S.
• Fussnoten: Published online: 2017 December 14 ; Gesehen am 10.09.2018
• Titel Quelle: Enthalten in: Molecular psychiatry
• Ort Quelle: [London] : Springer Nature, 1997
• Jahr Quelle: 2018
• Band/Heft Quelle: 23(2018), 3, Seite 621-628
• ISSN Quelle: 1476-5578
• DOI: doi:10.1038/mp.2017.112
• Datenträger: Online-Ressource
• Sprache: eng
• K10plus-PPN: 1580806422

Abstract

Ubiquitously expressed genes have been implicated in a variety of specific behaviors, including responses to ethanol. However, the mechanisms that confer this behavioral specificity have remained elusive. Previously, we showed that the ubiquitously expressed small GTPase Arf6 is required for normal ethanol-induced sedation in adult Drosophila. Here, we show that this behavioral response also requires Efa6, one of (at least) three Drosophila Arf6 guanine exchange factors. Ethanol-naïve Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared to wild-type flies. In contrast to wild type-flies, both Arf6 and Efa6 mutants preferred alcohol-containing food without prior ethanol experience. An analysis of the human ortholog of Arf6 and orthologs of Efa6 (PSD1-4) revealed that the minor G-allele of SNP rs13265422 in PSD3, as well as a haplotype containing rs13265422, were associated with increased frequency of drinking and binge drinking episodes in adolescents. The same haplotype was also associated with increased alcohol dependence in an independent European cohort. Unlike the ubiquitously expressed human Arf6 GTPase, PSD3 localization is restricted to the brain, particularly the prefrontal cortex (PFC). Functional magnetic resonance imaging (fMRI) revealed that the same PSD3 haplotype was also associated with a differential fMRI signal in the PFC during a Go/No-Go task, which engages PFC-mediated executive control. Our translational analysis therefore suggests that PSD3 confers regional specificity to ubiquitous Arf6 in the PFC to modulate human alcohol-drinking behaviors.