NK1R knockout mouse model and human genetics of Attention Deficit Hyperactivity Disorder

在英国，大约2%-5%的儿童和成年人患有注意力缺陷多动障碍(ADHD)。它的主要特征是多动、冲动和注意力不集中。ADHD是可遗传的，经常与其他精神问题共存，特别是酗酒和双相情感障碍(躁郁症)。一线用药包括被描述为精神刺激剂的药物？(例如安非他命)。然而，人们对它们的长期影响知之甚少，特别是对儿童的影响，迫切需要替代药物治疗。最近，我们发现了一种缺乏所谓NK1受体(NK1R基因敲除)的突变小鼠，它是过度活跃的。此外，这种惊人的行为可以通过治疗ADHD的药物来预防。基于这些发现，我们正在开发NK1R基因敲除小鼠作为ADHD的动物模型。在这个项目中，我们将通过研究这些小鼠是否冲动和/或注意力不集中以及多动来完善这个模型。我们还将测试我们的假设，即它们的异常行为是通过与ADHD相关的两个大脑区域中神经递质多巴胺和乙酰胆碱的调节中断来解释的。在这些小鼠研究的推动下，我们还发现了ADHD患者DNA中人类相当于NK1R基因(称为TACR1)的突变(单核苷酸多态)。我们的证据表明，这些基因多态性可以作为ADHD的诊断标志。TACR1基因的某些突变也可能增加ADHD患者对酒精中毒和/或双相情感障碍的易感性。在这个项目中，我们将定位ADHD患者DNA中的TACR1基因，并确认我们已确定的哪些突变与ADHD和/或酒精中毒或双相情感障碍有关。这些实验的综合结果将有助于完善使用突变(NKR1/-)小鼠作为ADHD亟需的动物模型，以及将TACR1基因突变作为ADHD的诊断测试。他们还将揭示NK1R/TACR1功能缺陷引起的大脑功能异常。所有这些信息将为未来旨在为ADHD开发新的治疗策略(包括一种新的药物治疗类别)的调查提供信息。

Attention Deficit Hyperactivity Disorder (ADHD) affects about 2-5% of children and adults in the UK. Its main features are hyperactivity, impulsivity and inattentiveness. ADHD is heritable and often co-exists with other psychiatric problems, especially alcoholism and bipolar disorder (manic depression). Front-line medication includes drugs that are described as ?psychostimulants? (e.g amphetamine). However, little is known about their long-term effects, especially in children, and there is a pressing need for alternative drug treatments. Recently, we discovered that a mutant mouse, which lacks so-called NK1 receptors (?NK1R knockout?), is hyperactive. Moreover, this striking behaviour is prevented by drugs used to treat humans with ADHD. Arising from these findings, we are developing the NK1R knockout mouse as an animal model of ADHD. In this project, we shall refine this model by investigating whether these mice are impulsive and/or inattentive, as well as hyperactive. We shall also test our proposal that their abnormal behaviour is explained by disrupted regulation of the neurotransmitters, dopamine and acetylcholine, in two brain regions that have been linked with ADHD. Prompted by these studies in mice, we have also discovered mutations (single nucleotide polymorphisms) in the human equivalent of the NK1R gene (known as TACR1) in DNA from patients with ADHD. Our evidence suggests that these polymorphisms can be used as a diagnostic marker for ADHD. It is also possible that certain mutations in the TACR1 gene increase susceptibility of ADHD patients to alcoholism and/or bipolar disorder. In this project, we shall map the TACR1 gene in DNA from ADHD patients and confirm which of the mutations we have identified are associated with ADHD and/or alcoholism or bipolar disorder. The combined results of these experiments will help to refine the use of both mutant (NKR1 /-) mice, as a much needed animal model of ADHD, and mutations in the TACR1 gene as a diagnostic test for ADHD. They will also cast light on the functional abnormalities in the brain arising from a deficit in NK1R/TACR1 function. All this information will inform future investigations aimed at developing novel treatment strategies (including the potential for a new class of drug treatment) for ADHD.