Development of A Novel Animal Model of Tardive Dyskinesia

描述（由申请人提供）：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）的动物模型。抗精神病药物已经彻底改变了精神分裂症的治疗方法，但不幸的是，它的副作用是发展为TD，一种使人衰弱的多动运动障碍。“典型的”第一代抗精神病药物产生TD的责任在50多年前就被认识到了。然而，除了一个必要因素是纹状体中D2样多巴胺受体（D2R）表达的慢性阻断外，对其潜在的病理生理学知之甚少。虽然第二代“非典型”药物产生TD的风险显著降低，但最近发表的临床研究（如CATIE）的结果强调了它们与致命性心血管和代谢紊乱的关联，并建议在精神分裂症的药物治疗中重新发挥典型药物的作用。然而，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：咀嚼空虚的啮齿动物模型和更类似的灵长类动物模型效率极低且昂贵——大量动物被治疗数月至数年，以产生足够多的具有TD样症状的动物。因此，开发一种实用、可靠、廉价的TD小鼠模型将对改善精神分裂症药物治疗做出重要贡献。这项研究的基本原理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的发展中至关重要。其中包括以下意见：1) RGS9-2在纹状体中特异性表达，纹状体是控制运动和脑结构的基底神经节环的重要组成部分，在TD病因学中至关重要；2)RGS9-2特异性与D2R共定位，D2R是抗精神病药物的主要靶点，并特异性调节D2R激活的纹状体信号通路；3)RGS9-2敲除小鼠仅在氟啶醇治疗3天后就出现了类似TD的高运动性异常不自主运动（AIMs）。一种典型的抗精神病药。在这里，我们提出验证RGS9基因敲除小鼠具有病原学有效性的假设，并模拟临床情况。TD的一个重要病因特征是，它是由高亲和力阻断D2R的药物（如较老的典型抗精神病药物）产生的，而低亲和力阻断剂（如第二代抗精神病药物）产生的TD发病率较低。此外，一旦出现TD，它不容易通过停止药物治疗来逆转。我们将确定基因敲除小鼠模型中是否保留了TD的这些关键临床特征。我们还将在小鼠模型中测试外源性病毒介导的RGS9-2纹状体表达是否可以抑制抗精神病药物诱导的AIMs。该实验将有助于证实改变小鼠模型成年纹状体中RGS9-2水平可改变抗精神病药物诱导的AIMs易感性，并为TD的治疗提供策略。

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.