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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior
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Autism gene variant causes hyperserotonemia, serotonin receptor hypersensitivity, social impairment and repetitive behavior

机译:自闭症基因变异会导致高血清素血症,5-羟色胺受体超敏反应,社交障碍和重复行为

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摘要

Fifty years ago, increased whole-blood serotonin levels, or hyperserotonemia, first linked disrupted 5-HT homeostasis to Autism Spectrum Disorders (ASDs). The 5-HT transporter (SERT) gene (SLC6A4) has been associated with whole blood 5-HT levels and ASD susceptibility. Previously, we identified multiple gain-of-function SERT coding variants in children with ASD. Here we establish that transgenic mice expressing the most common of these variants, SERT Ala56, exhibit elevated, p38 MAPK-dependent transporter phosphorylation, enhanced 5-HT clearance rates and hyperserotonemia. These effects are accompanied by altered basal firing of raphe 5-HT neurons, as well as 5HT_(1A) and 5HT_(2A) receptor hypersensitivity. Strikingly, SERT Ala56 mice display alterations in social function, communication, and repetitive behavior. Our efforts provide strong support for the hypothesis that altered 5-HT homeostasis can impact risk for ASD traits and provide a model with construct and face validity that can support further analysis of ASD mechanisms and potentially novel treatments.
机译:五十年前,全血5-羟色胺水平升高或高血清素血症首先将5-HT动态平衡与自闭症谱系障碍(ASD)联系起来。 5-HT转运蛋白(SERT)基因(SLC6A4)与全血5-HT水平和ASD敏感性相关。以前,我们在患有ASD的儿童中发现了多种功能增益SERT编码变体。在这里我们建立表达这些变体中最常见的SERT Ala56的转基因小鼠表现出升高的p38 MAPK依赖性转运蛋白磷酸化,增强的5-HT清除率和高血清素血症。这些作用伴随着5-HT神经元基础放电的改变,以及5HT_(1A)和5HT_(2A)受体超敏反应。令人惊讶的是,SERT Ala56小鼠显示出社交功能,沟通和重复行为的改变。我们的努力为改变5-HT稳态可能影响ASD性状风险的假说提供了有力支持,并提供了具有结构和脸部有效性的模型,可以支持对ASD机制和潜在新疗法的进一步分析。

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  • 作者单位

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232,Departments of Pediatrics, Vanderbilt University, Nashville, TN 37232,Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232,Departments of Brain Institute, and Vanderbilt University, Nashville, TN 37232,Departments of Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232;

    Departments of PhysiologyUniversity of Texas Health Science Center, San Antonio, TX 78229;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232;

    Departments of Neurosciences, and University of Texas Health Science Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Departments of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229,Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229;

    Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232,Departments of Brain Institute, and Vanderbilt University, Nashville, TN 37232,Departments of Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232;

    Laboratory of Behavioral Neuroscience, National Institute of Mental Health, Bethesda, MD 20892;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232,Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232,Departments of Brain Institute, and Vanderbilt University, Nashville, TN 37232,Departments of Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232,Silvio O. Conte Center for Neuroscience Research, Vanderbilt University, Nashville, TN 37232;

    Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232,Departments of Brain Institute, and Vanderbilt University, Nashville, TN 37232,Departments of Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232,Silvio O. Conte Center for Neuroscience Research, Vanderbilt University, Nashville, TN 37232,Department of Biological Sciences, Vanderbilt University, Nashville, TN 37232;

    Departments of Neurosciences, and University of Texas Health Science Center, San Antonio, TX 78229;

    Departments of PhysiologyUniversity of Texas Health Science Center, San Antonio, TX 78229,Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232,Departments of Brain Institute, and Vanderbilt University, Nashville, TN 37232,Departments of Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232,Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN 37232;

    Departments of Psychiatry, Vanderbilt University, Nashville, TN 37232,Departments of Pharmacology, Vanderbilt University, Nashville, TN 37232,Departments of Brain Institute, and Vanderbilt University, Nashville, TN 37232,Departments of Kennedy Center for Research on Human Development, Vanderbilt University, Nashville, TN 37232,Silvio O. Conte Center for Neuroscience Research, Vanderbilt University, Nashville, TN 37232;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    development; monoamine; neurotransmitter;

    机译:发展一元胺神经递质;

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