Development of A Novel Animal Model of Tardive Dyskinesia

描述(申请人提供)：本研究的目的是验证RGS9基因敲除小鼠作为迟发性运动障碍(TD)动物模型的有效性。抗精神病药物给精神分裂症的治疗带来了革命性的变化，但一个不幸的副作用是TD的发展，这是一种衰弱的多动障碍。“典型的”第一代抗精神病药物生产TD的责任早在50多年前就被认识到了。然而，除了一个必要的因素是纹状体表达的D2样多巴胺受体(D2R)的慢性阻断之外，人们对其潜在的病理生理学了解很少。虽然第二代“非典型”药物显著降低了发生TD的风险，但最近发表的CATIE等临床研究结果强调了它们与致命的心血管和代谢紊乱的关系，并表明典型药物在精神分裂症的药物治疗中将重新发挥作用。然而，这些典型药物的重新使用关键取决于更好地理解、管理和治疗其潜在的不可逆转和严重的副作用TD。理解、管理和治疗TD的一个主要障碍是缺乏实用的动物模型：空洞的咀嚼啮齿动物模型和更类似的灵长类动物模型效率极低且成本高昂-大量动物被治疗数月至数年，以产生足够的具有TD样症状的动物。因此，发展一种实用、可靠、廉价的TD小鼠模型将对提高精神分裂症的药物治疗水平做出重要贡献。这项研究的理论基础在于这位首席研究员和其他人最近发表的数据，这些数据表明，大脑RGS蛋白RGS9-2在TD的发展中起着关键作用。这些结果包括：1)RGS9-2特异地表达于纹状体--纹状体是控制运动和脑结构的基础神经节回路的重要组成部分，在TD病因学中至关重要；2)RGS9-2与D2R特异地共存，D2R是抗精神病药物的主要靶点，特异性调节D2R激活的纹状体信号通路；3)RGS9-2基因敲除小鼠在氟哌啶醇(一种典型的抗精神病药物)仅治疗三天后就出现了类似TD的高动力异常不自主运动(AIMS)。在这里，我们建议检验RGS9基因敲除小鼠具有病因学有效性的假设，并对临床情况进行模拟。TD的一个重要病因学特征是，它是由具有高亲和力的阻断D2R的药物(例如较老的典型抗精神病药物)产生的，而亲和力较低的阻滞剂(例如第二代抗精神病药物)导致TD的发生率较低。此外，一旦出现TD，停止药物治疗就不容易逆转。我们将确定TD的这些关键临床特征是否在基因敲除小鼠模型中保留下来。我们还将测试外源性病毒介导的RGS9-2在小鼠模型中的纹状体表达是否可以抑制抗精神病药物诱导的AIMS。这样的实验将有助于证实，改变成年小鼠模型纹状体中的RGS9-2水平可以改变对抗精神病药物诱导的目标的敏感性，并为治疗TD指明了一种策略。 与公共卫生相关：限制用于治疗精神分裂症的药物的有效性的一个主要的虚弱和不可逆转的副作用是发展称为迟发性运动障碍(TD)的不自主运动。由于缺乏方便的动物模型，人们对TD的发生机制和治疗方法知之甚少。本申请描述了一种缺乏一种名为RGS9-2的蛋白质的功能基因的小鼠品系的开发和验证，作为研究和学习治疗TD的一种新的、方便的动物模型。

DESCRIPTION (provided by applicant): The objective of this study is to validate the RGS9 knockout mouse as an animal model for tardive dyskinesia (TD). Antipsychotic drugs have revolutionized the treatment of schizophrenia, but an unfortunate side-effect is the development of TD, a debilitating hyperkinetic movement disorder. The liability of "typical" first-generation antipsychotic drugs to produce TD was recognized more than 50 years ago. Yet, very little of the underlying pathophysiology is understood other than that a necessary factor is the chronic blockade of D2- like dopamine receptors (D2R) expressed in the striatum. While the second-generation "atypical" drugs have a significantly reduced risk for producing TD, recently published results from clinical studies such as CATIE have emphasized their association with fatal cardiovascular and metabolic disorders and suggest a renewed role for the typical drugs in the pharmacotherapy of schizophrenia. However, the renewed use of the typical drugs depends critically on better understanding, managing and treating their potentially irreversible and serious side- effect, TD. A major impediment for understanding, managing and treating TD has been the lack of a practical animal model: the vacuous chewing rodent model and the more analogous primate model are extremely inefficient and expensive-large numbers of animals are treated for months to years to produce enough animals with TD-like symptoms. Thus the development of a useful, reliable and inexpensive mouse model of TD will be an important contribution to improving schizophrenia pharmacotherapy. The rationale for this study lies in data recently published by this principal investigator and others which suggest that a brain RGS protein, RGS9-2, is critical in the development of TD. They include the following observations: 1) RGS9-2 is expressed specifically in the striatum, an important component of the basal ganglia loop that controls movement and the brain structure that is critical in TD etiology, 2) RGS9-2 specifically colocalizes with D2R, the major target of antipsychotic drugs and specifically modulates D2R-activated striatal signaling pathways and 3) RGS9-2 knock-out mice developed hyperkinetic abnormal involuntary movements (AIMs) resembling TD after only three days of treatment with haloperidol, a typical antipsychotic drug. Here we propose to test the hypothesis that the RGS9 knockout mouse has etiological validity and models the clinical condition. An important etiological feature of TD is that it is produced by drugs that block D2R with high affinity (e.g. older typical antipsychotics), and lower affinity blockers (e.g. second generation antipsychotics) produce a lower incidence of TD. In addition once TD develops it is not easily reversed by cessation of drug-treatment. We will determine if these key clinical features of TD are preserved in the knockout mouse model. We will also test if exogenous viral-mediated striatal expression of RGS9-2 in the mouse model can suppress antipsychotic- induced AIMs. Such an experiment will help to confirm that altering RGS9-2 levels in adult striatum of the mouse model alters susceptibility to antipsychotic-induced AIMs and point to a strategy for treating TD. PUBLIC HEALTH RELEVANCE: A major debilitating and irreversible side-effect that limits the usefulness of drugs used to treat schizophrenia is the development of involuntary movements called tardive dyskinesia (TD). Very little is known about how TD occurs and how to treat it because of the lack of a convenient animal model. This application describes the development and validation of a mouse strain that lacks a functional gene for a protein called, RGS9-2, as a novel and convenient animal model for studying and learning to treat TD.