Original Article | Published:

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

Molecular Psychiatry volume 23, pages 621628 (2018) | Download Citation

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-naive Arf6 and Efa6 mutants were sensitive to ethanol-induced sedation and lacked rapid tolerance upon re-exposure to ethanol, when compared with 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 single nucleotide polymorphism (SNP) rs13265422 in PSD3, as well as a haplotype containing rs13265422, was associated with an 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 revealed that the same PSD3 haplotype was also associated with a differential functional magnetic resonance imaging 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.

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Acknowledgements

We thank the Bloomington stock center, and Yang Hong (University of Pittsburgh) for fly strains, and Michael Buszczak, Helmut Krämer and Rothenfluh lab members for helpful discussions. This work was supported by the NIH (T32 fellowships DA007290 to DAG and JHP, F32 AA021340 to SAO, K08 DK091316 to ARR, R01 AA019526 and R21 AA022404 to AR), the European Union-funded FP6 Integrated Project IMAGEN (Reinforcement-related behavior in normal brain function and psychopathology; LSHM-CT-2007–037286), the FP7 projects IMAGEMEND (602450) and MATRICS (603016), the Innovative Medicine Initiative Project EU-AIMS (115300-2), the European Research Council Award ‘STRATIFY’ as well as the Medical Research Council Programme Grant ‘Developmental pathways into adolescent substance abuse’ (93558). Further support was provided by the Swedish Funding Agency FORMAS, the MRC-ICMR Newton project ‘Consortium on Vulnerability to Externalizing Disorders and Addictions’ (c-VEDA) (MR/N000390/1), the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London, the German Bundesministerium für Bildung und Forschung (BMBF grants 01GS08152; 01EV0711; eMED SysAlc 01ZX1311A; Forschungsnetz AERIAL), the NIH (R01 MH085772-01A1), as well as the NIH-BD2K (Big Data to Knowledge) grant U54 EB020403–ENIGMA Center for Worldwide Medicine, Imaging and Genomics. AR was also supported by an Effie Marie Cain Scholarship in Biomedical Research from UT Southwestern Medical Center Dallas.

Author contributions

DAG, JHP, SAO, SFA and AR conceived, performed and analyzed the Drosophila experiments. SD, TB, CB, ALWB, PJC, HF, BI, ML, JM, TP, MS, GS and the IMAGEN consortium acquired the human data. TJ, BX and GS analyzed the human data. DAG, TJ, JHP, JLH, ARR, GS and AR wrote the paper.

Author information

Author notes

    • D A Gonzalez

    Current address: Nueces County Health District, Corpus Christi Hospital and Health Care, Corpus Christi, TX, USA.

    • D A Gonzalez
    •  & T Jia

    These authors contributed equally to this work.

    • J H Pinzón

    Current address: Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.

    • S F Acevedo

    Current address: Thomas J Stephens and Associates, Richardson, TX, USA.

    • S A Ojelade

    Current address: Department of Neurology, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

    • G Schumann
    •  & A Rothenfluh

    These authors co-supervised the study.

Affiliations

  1. Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • D A Gonzalez
    • , J H Pinzón
    • , S F Acevedo
    • , S A Ojelade
    •  & A Rothenfluh
  2. Program in Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • D A Gonzalez
    • , S A Ojelade
    •  & A Rothenfluh
  3. Institute of Psychiatry, King's College London, London, UK

    • T Jia
    • , B Xu
    • , N Tay
    • , S Desrivières
    •  & G Schumann
  4. MRC Social, Genetic and Developmental Psychiatry Centre, London, UK

    • T Jia
    • , B Xu
    • , N Tay
    • , S Desrivières
    • , P J Conrod
    •  & G Schumann
  5. Department of Psychiatry, Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA

    • J L Hernandez
    •  & A Rothenfluh
  6. Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    • T Banaschewski
  7. Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany

    • C Büchel
  8. Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland

    • A L W Bokde
  9. Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada

    • P J Conrod
  10. Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany

    • H Flor
  11. Neurospin, Commissariat à l'Energie Atomique, Gif-sur-Yvette, France

    • V Frouin
  12. Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany

    • J Gallinat
  13. Department of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA

    • H Garavan
  14. Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK

    • P A Gowland
  15. Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité—Universitätsmedizin Berlin, Berlin, Germany

    • A Heinz
  16. Physikalisch-Technische Bundesanstalt, Braunschweig and Berlin, Germany

    • B Ittermann
  17. McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada

    • M Lathrop
  18. Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 ‘Imaging & Psychiatry’, University Paris Sud, Paris, France

    • J-L Martinot
  19. AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris, France

    • J-L Martinot
  20. School of Psychology, University of Nottingham, Nottingham, UK

    • T Paus
  21. Rotman Research Institute, University of Toronto, Toronto, ON, Canada

    • T Paus
  22. Montreal Neurological Institute, McGill University, Montreal, QC, Canada

    • T Paus
  23. Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany

    • M N Smolka
  24. Department of Psychology, Neuroimaging Center, Technische Universität Dresden, Dresden, Germany

    • M N Smolka
  25. Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA

    • A R Rodan
  26. Division of Nephrology, Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA

    • A R Rodan

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Competing interests

TB served in an advisory or consultancy role for Hexal Pharma, Lilly, Medice, Novartis, Otsuka, Oxford Outcomes, PCM Scientific, Shire and Viforpharma. TB received conference attendance support and conference support or speaker’s fees from Lilly, Medice, Novartis and Shire. TB is/has been involved in clinical trials conducted by Shire and Viforpharma. JG has received research funding from AstraZeneca, Eli Lilly & Co., Janssen-Cilag and Bristol-Myers Squibb, and speaker’s fees from AstraZeneca, Janssen-Cilag and Bristol-Myers Squibb. The remaining authors declare no conflict of interest.

Corresponding authors

Correspondence to G Schumann or A Rothenfluh.

Supplementary information

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DOI

https://doi.org/10.1038/mp.2017.112

Supplementary Information accompanies the paper on the Molecular Psychiatry website (http://www.nature.com/mp)