Suicide Endophenotypes and Molecular Mechanisms of Lithium Action

描述(申请人提供)：自杀对受害者、他们的大家庭以及美国和世界各地的公共健康都有毁灭性的影响。很少有治疗方法被证明能降低风险。有一个例外，得到了大量临床证据的支持，那就是锂在降低自杀未遂和自杀完成的风险方面都是有效的。然而，锂的抗自杀作用的潜在机制尚不清楚，这限制了改进预防方法的发展。我们打算用小鼠作为一个模式生物来阐明锂与人类自杀相关的生物和行为因素相互作用的分子途径。然而，与其尝试在小鼠身上模拟自杀这一不可行的任务，我们将专注于在与自杀相关的测试中评估小鼠行为的方法，这些测试与包括攻击性和冲动性在内的自杀相关的内表型(复杂行为表型的解构成分)。这些内表型将与人类遗传、生化和药理学研究结果相结合用于自杀研究，以提供构建有效的动物模型。为此，临床研究已经发现包括神经元型一氧化氮合酶(NOS1)在内的一些基因的多态与冲动、攻击性和自杀有关。同样，广泛的研究结果表明，在自杀行为的病因中，5-羟色胺(5-HT)神经传递的缺陷以及冲动和攻击性的增加。来自临床前和人类遗传学研究的数据表明，锂可能通过抑制糖原合成酶-3！(GSK-3！)有趣的是，新兴的基础科学证据将NOS1功能、5-羟色胺神经传递和GSK-3联系在一起！活动表明，它们可能在与自杀等精神疾病的病因和治疗相关的病理生理过程中存在因果联系，在这些疾病中，冲动和攻击性起着作用。因此，我们的具体目标是：1)确定锂对遗传和药物诱导的5-羟色胺水平降低的小鼠行为的影响；2)确定锂对一氧化氮合酶1(NOS1)活性遗传和药物介导的缺陷小鼠行为的影响；3)评估锂的直接靶点糖原合成酶3！在改变5-羟色胺和NOS1功能降低所介导的行为中的作用。这些研究将利用目前对锂的药理学知识，并使用小鼠基因敲除和药理学方法来剖析锂可能改变冲动和攻击行为的分子和神经生物学机制，以及确定锂和已知与自杀有关的生物标记物之间的相互作用点。公共卫生相关性：从这些研究中得出的数据应该促进改进的药物干预措施的发展，以改变攻击性和冲动性行为，从而降低所有诊断类别的自杀风险。 公共卫生相关性：完全自杀对家庭、社会和公共健康都有毁灭性的影响。很少有治疗被证明能降低风险；然而，锂治疗在降低自杀未遂和自杀完成风险方面是有效的，原因不明。这项申请建议在内表型策略的背景下进行实验，这些实验将揭示锂发挥其治疗作用的分子机制。

DESCRIPTION (provided by applicant): Suicide has a devastating impact on victims, their extended families, and public health in the United States, as well as throughout the world. Few treatments have been shown to reduce risk. An exception, supported by extensive clinical evidence, is that lithium is effective in reducing the risk of both attempted and completed suicide. However, the mechanisms underlying lithium's antisuicidal actions are not yet known, limiting the development of improved prevention approaches. We intend to use the mouse as a model organism to elucidate molecular pathways by which lithium interacts with biological and behavioral factors associated with suicide in humans. However, rather than attempting the infeasible task of modeling suicide in mice, we will focus on approaches that assess mouse behavior in tests relevant to well validated endophenotypes (deconstructed components of complex behavioral phenotypes) associated with suicide including aggression and impulsivity. These endophenotypes will be used in combination with human genetic, biochemical, and pharmacological findings in suicide research to provide construct-valid animal models. Toward this end, clinical studies have implicated polymorphisms in a number of genes, including neuronal nitric oxide synthase (NOS1), with measures of impulsivity, aggression, and suicide. Similarly, the results of extensive research have implicated deficits in serotonin (5-HT) neurotransmission in the etiology of suicidal behavior as well as increased impulsivity and aggression. Data from preclinical and human genetic studies indicate that lithium may exert some of its mood stabilizing effects through inhibition of the enzyme glycogen synthase kinase-3! (GSK-3!). Intriguingly, emerging basic science evidence links NOS1 function, 5-HT neurotransmission, and GSK-3! activity suggesting that they may be causally linked in the pathophysiological processes relevant to the etiology and treatment of psychiatric diseases such as suicide, where impulsivity and aggression play a role. Thus, our Specific Aims are to: 1) Identify the effects of lithium on behavior in mice with genetically- and pharmacologically-induced decreases in 5-HT levels; 2) Identify the effects of lithium on behavior in mice with genetically- and pharmacologically-mediated deficiencies in nitric oxide synthase 1 (NOS1) activity; 3) Evaluate the role of glycogen synthase kinase-3!, a direct target of lithium, in modifying behaviors mediated by decreased 5-HT and NOS1 function. These studies will capitalize on current knowledge of lithium pharmacology and use mouse genetic knockouts and pharmacological approaches to dissect the molecular and neurobiological mechanisms whereby lithium may modify impulsive and aggressive behavior as well identify points of interaction between lithium and biological markers known to be associated with suicide. Public Health Relevance: The data derived rom these studies should promote the development of improved pharmacological interventions to modify aggressive and impulsive behaviors thereby decreasing the risk of suicide across all diagnostic categories. PUBLIC HEALTH RELEVANCE: A completed suicide has a devastating impact on families, society, and public health. Few treatments have been shown to result in reduced risk; however, lithium treatment is effective, for unknown reasons, in reducing the risk of both attempted and completed suicide. This application proposes experiments in the context of endophenotype strategies that will reveal molecular mechanisms whereby lithium acts to exert its therapeutics effects.