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首页> 外文学位 >Serotonin 2C Receptor mRNA editing as a Molecular Correlate of Suicide.
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Serotonin 2C Receptor mRNA editing as a Molecular Correlate of Suicide.

机译：血清素2C受体mRNA编辑为自杀的分子相关分子。

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摘要

Suicide---the tenth leading cause of death in the U.S.---is a complex phenomenon with numerous biological and psychological risk factors. The presence of a psychiatric diagnosis---commonly major depression disorder (MDD), bipolar disorder (BPD), schizophrenia (SZ), or drug abuse---is the most consistent risk factor for suicide in the general population (Cavanagh et al., 2003; Nock et al., 2008). Genetic studies indicate that suicidal behavior is characterized by its own distinct pathophysiology, which is different from and/or independent of associated comorbid psychiatric conditions (Brent and Mann, 2005; Voracek and Loibl, 2007). One of the biological mechanisms that is associated with suicide is related to variations in RNA editing of the serotonin 2C receptor (5-HT2CR) in the brain (Dracheva et al., 2008; Gurevich et al., 2002b; Iwamoto and Kato, 2003; Niswender et al., 2001). Specifically, our lab has previously shown that suicide victims with an antemortem diagnosis of SZ or BPD have a higher level of 5-HT2CR mRNA editing (and by inference, a lower level of the receptor function) in the dorsolateral prefrontal cortex (DLPFC) compared to individuals of the same diagnosis that died of other causes (Dracheva et al., 2008). The molecular mechanisms of these observed editing alterations, however, remain elusive.;In an attempt to identify these mechanisms, I developed and evaluated a novel multiplex TaqMan qPCR editing assay and used it to investigate whether the observed suicide-associated alterations in 5-HT2CR editing may result from increased activity of the enzymes that catalyze mRNA editing, adenosine deaminases that act on RNA (ADARs). I found that the suicide-associated editing alteration is apparently unique to the 5-HT2CR, as editing of other ADAR substrates, ionotropic glutamate receptor subunits (iGluRs) and ADAR2, remained unchanged in the DLPFC of BPD and SZ suicides. In addition, through the course of this study, I made an important observation with respect to the editing patterns of specific iGluR alternative splicoforms in the human brain. The interplay between editing and splicing which I detected in these iGluR subunits may play a significant role in moderating the sensitivity of the resulting receptor to glutamate.;Basal extracellular serotonin has been proposed as a potential trigger for the modulation of 5-HT2CR editing efficiency. Because of the importance of serotonergic system in suicide, I investigated this hypothesis by comparing 5-HT2CR editing among rodent and human models of altered extracellular serotonin [serotonin transporter (SERT) knock-out rats and humans with different functional SERT and monoamine oxidase A polymorphisms]. My findings argue against the notion that extracellular serotonin availability triggers 5-HT2CR editing alterations. Instead, editing may serve as a homeostatic mechanism that adjusts 5-HT2CR function in order to compensate for a possible detrimental effect of genetic polymorphisms within genes whose products comprise the 5-HT2CR functional network. To begin testing this hypothesis, I compared 5-HT2CR editing patterns among individuals with different 5-HT2CR SNPs genotypes. Although only trend level associations between editing and these 5-HT2CR genotypes were observed, other SNPs within the gene may prove to be significantly associated with higher 5-HT2CR editing.;Since thirty percent of all suicides occur in the context of an MDD diagnosis (Cornelius et al., 1995; Oquendo et al., 2004) and there is evidence linking MDD to dysfunction of the serotonin system (Frisch et al., 1999; Maes and Meltzer, 1995; Owens and Nemeroff, 1994; Stockmeier et al., 1998), I assessed the 5-HT2CR editing in the DLPFC of a cohort of MDD subjects and detected suicide-associated changes similar to those previously noted in BPD and SZ suicides. This finding confirmed that increased 5-HT2CR editing in the DLPFC is a suicide-specific phenomenon, consistent throughout the three most common comorbid disorders.
机译：自杀-美国第十大死亡原因-是一种复杂的现象，具有许多生物学和心理风险因素。精神病诊断-通常是重度抑郁症（MDD），双相情感障碍（BPD），精神分裂症（SZ）或药物滥用-是普通人群中自杀的最一致危险因素（Cavanagh等（2003； Nock等，2008）。遗传研究表明，自杀行为以其自身独特的病理生理学为特征，这不同于和/或独立于相关的合并性精神疾病（Brent和Mann，2005； Voracek和Loibl，2007）。与自杀有关的生物学机制之一与大脑中血清素2C受体（5-HT2CR）的RNA编辑变化有关（Dracheva等，2008; Gurevich等，2002b; Iwamoto and Kato，2003 ； Niswender等，2001）。具体而言，我们的实验室先前表明，与死前诊断为SZ或BPD的自杀受害者相比，背外侧前额叶皮层（DLPFC）的5-HT2CR mRNA编辑水平较高（据推断，受体功能水平较低）诊断相同的个体而死于其他原因（Dracheva等，2008）。然而，这些观察到的编辑改变的分子机制仍然难以捉摸。为了确定这些机制，我开发并评估了一种新型的TaqMan qPCR多重多重编辑分析方法，并用于研究在5-HT2CR中是否观察到与自杀有关的改变。编辑可能是由催化mRNA编辑的酶（作用于RNA（ADAR）的腺苷脱氨酶）的活性增强所致。我发现与自杀相关的编辑改变显然是5-HT2CR特有的，因为其他ADAR底物，离子型谷氨酸受体亚单位（iGluRs）和ADAR2的编辑在BPD和SZ自杀的DLPFC中保持不变。此外，在本研究过程中，我对人脑中特定iGluR替代splicoforms的编辑模式进行了重要观察。我在这些iGluR亚基中检测到的编辑和剪接之间的相互作用可能在调节所得受体对谷氨酸的敏感性中起重要作用。基础细胞外血清素被认为是调节5-HT2CR编辑效率的潜在诱因。由于血清素能系统在自杀中的重要性，我通过比较啮齿动物模型和人类模型中改变的细胞外血清素[5-羟色胺转运蛋白（SERT）敲除大鼠和具有不同功能SERT和单胺氧化酶A多态性的人类]对5-HT2CR编辑进行了研究，从而研究了这一假设]。我的发现与细胞外血清素可用性触发5-HT2CR编辑改变的观点背道而驰。相反，编辑可以用作调节5-HT2CR功能的体内平衡机制，以补偿其产物包含5-HT2CR功能网络的基因中遗传多态性的可能有害作用。为了开始检验该假设，我比较了具有不同5-HT2CR SNP基因型的个体之间的5-HT2CR编辑模式。尽管只观察到编辑与这些5-HT2CR基因型之间的趋势水平相关性，但该基因中的其他SNP可能与更高的5-HT2CR编辑显着相关。;由于所有自杀中有30％发生在MDD诊断的背景下（ Cornelius等，1995； Oquendo等，2004），并且有证据表明MDD与5-羟色胺系统功能障碍有关（Frisch等，1999； Maes和Meltzer，1995； Owens和Nemeroff，1994； Stockmeier等。 （1998年），我评估了一批MDD受试者在DLPFC中进行的5-HT2CR编辑，并发现了与自杀相关的变化，与先前在BPD和SZ自杀中提到的变化相似。这一发现证实，在DLPFC中增加的5-HT2CR编辑是自杀特有的现象，在三种最常见的合并症中均一致。

著录项

  • 作者

    Lyddon, Rebecca.;

  • 作者单位

    Mount Sinai School of Medicine.;

  • 授予单位 Mount Sinai School of Medicine.;
  • 学科 Biology Neuroscience.;Biology Molecular.;Psychology Psychobiology.;Health Sciences Mental Health.
  • 学位 Ph.D.
  • 年度 2012
  • 页码 135 p.
  • 总页数 135
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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