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

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The Arf6 activator Efa6/PSD3 confers regional specificity and modulates ethanol consumption in Drosophila and humans.
Molecular Psychiatry ( IF 11.0 ) Pub Date : 2018-03-01 , DOI: 10.1038/mp.2017.112
D A Gonzalez _{1,

2} , T Jia _{3,

4} , J H Pinzón ₁ , S F Acevedo ₁ , S A Ojelade _{1,

2} , B Xu _{3,

4} , N Tay _{3,

4} , S Desrivières _{3,

4} , J L Hernandez ₅ , T Banaschewski ₆ , C Büchel ₇ , A L W Bokde ₈ , P J Conrod _{4,

9} , H Flor ₁₀ , V Frouin ₁₁ , J Gallinat ₁₂ , H Garavan ₁₃ , P A Gowland ₁₄ , A Heinz ₁₅ , B Ittermann ₁₆ , M Lathrop ₁₇ , J-L Martinot _{18,

19} , T Paus _{20,

21,

22} , M N Smolka _{23,

24} , , A R Rodan _{25,

26} , G Schumann _{3,

4} , A Rothenfluh _{1,

2,

5}

Affiliation

Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Program in Neuroscience, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Institute of Psychiatry, King's College London, London, UK.
MRC Social, Genetic and Developmental Psychiatry Centre, London, UK.
Department of Psychiatry, Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.
Department of Child and Adolescent Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Universitätsklinikum Hamburg Eppendorf, Hamburg, Germany.
Institute of Neuroscience, Trinity College Dublin, Dublin, Ireland.
Department of Psychiatry, Université de Montreal, CHU Ste Justine Hospital, Montreal, QC, Canada.
Department of Cognitive and Clinical Neuroscience, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.
Neurospin, Commissariat à l'Energie Atomique, Gif-sur-Yvette, France.
Department of Psychiatry and Psychotherapy, University Medical Center Hamburg-Eppendorf (UKE), Hamburg, Germany.
Department of Psychiatry and Psychology, University of Vermont, Burlington, VT, USA.
Sir Peter Mansfield Imaging Centre School of Physics and Astronomy, University of Nottingham, University Park, Nottingham, UK.
Department of Psychiatry and Psychotherapy, Campus Charité Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Physikalisch-Technische Bundesanstalt, Braunschweig and Berlin, Germany.
McGill University and Genome Quebec Innovation Centre, Montreal, QC, Canada.
Institut National de la Santé et de la Recherche Médicale, INSERM CEA Unit 1000 'Imaging & Psychiatry', University Paris Sud, Paris, France.
AP-HP Department of Adolescent Psychopathology and Medicine, Maison de Solenn, University Paris Descartes, Paris, France.
School of Psychology, University of Nottingham, Nottingham, UK.
Rotman Research Institute, University of Toronto, Toronto, ON, Canada.
Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
Department of Psychiatry and Psychotherapy, Technische Universität Dresden, Dresden, Germany.
Department of Psychology, Neuroimaging Center, Technische Universität Dresden, Dresden, Germany.
Division of Nephrology, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Division of Nephrology, Department of Internal Medicine, Molecular Medicine Program, University of Utah, Salt Lake City, UT, USA.

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.

中文翻译：

Arf6 激活剂 Efa6/PSD3 赋予区域特异性并调节果蝇和人类的乙醇消耗。

普遍表达的基因与多种特定行为有关，包括对乙醇的反应。然而，赋予这种行为特异性的机制仍然难以捉摸。以前，我们发现普遍表达的小 GTPase Arf6 是成年果蝇中正常乙醇诱导的镇静所必需的。在这里，我们表明这种行为反应还需要 Efa6，（至少）三个果蝇 Arf6 鸟嘌呤交换因子之一。与野生型果蝇相比，未使用乙醇的 Arf6 和 Efa6 突变体对乙醇诱导的镇静作用敏感，并且在再次接触乙醇后缺乏快速耐受性。与野生型果蝇相比，Arf6 和 Efa6 突变体都喜欢没有事先乙醇经验的含酒精食物。对人类 Arf6 直系同源物和 Efa6 直系同源物 (PSD1-4) 的分析表明，PSD3 中单核苷酸多态性 (SNP) rs13265422 的次要 G 等位基因以及包含 rs13265422 的单倍型与饮酒频率增加有关和青少年暴饮暴食。在一个独立的欧洲队列中，相同的单倍型也与酒精依赖增加有关。与普遍表达的人类 Arf6 GTPase 不同，PSD3 定位仅限于大脑，尤其是前额叶皮层 (PFC)。功能磁共振成像显示，在执行/不执行任务期间，相同的 PSD3 单倍型也与 PFC 中的差异功能磁共振成像信号相关，该任务涉及 PFC 介导的执行控制。因此，我们的翻译分析，

更新日期：2018-02-21

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