Targeting Glial mGluR5 in Schizophrenia

描述(申请人提供)：精神分裂症是一种多因素疾病，有几种理论可供推测。还有一种假设是，怀孕期间的病毒感染可能会改变或引发胎儿大脑发育不正常。事实上，产前注射脂多糖或Poly I：C在一定程度上会导致啮齿动物模型在以后的生活中感觉运动门控缺陷和运动对精神刺激剂的敏化。这是精神分裂症患者的两个特点。有趣的是，最近的研究表明，谷氨酸能代谢性受体5(MGluR5)与感觉运动门控反应中断和精神刺激剂诱导的运动活动改变有关。MGluR5定位于神经元和神经胶质细胞。其表达的变化可反映神经元活动的功能变化或参与炎症反应，可作为新的治疗靶点。目的1.探讨多聚I：C免疫攻击精神分裂症动物模型中mGluR5与炎症反应的关系。我们假设Poly I：C的作用将促进小胶质细胞的激活和炎性介质的释放，进一步加重由毒素造成的神经病理状况。怀孕第9天的雌性小鼠将被注射一定剂量的Poly I：C或生理盐水。结合行为学研究，将在两个时间点(p35(青春期前)和p80(成年期))进行使用[11C]PK11195对炎症反应的microPET成像研究和使用[18F]FPEB对mGluR5表达的调节，以将炎症的时间进程与运动功能障碍以及炎症反应/mGluR5功能调节的程度联系起来。还将对怀孕的雌性进行成像，以评估接受治疗的母亲和发育中的幼崽的这些反应。终点成像研究将与尸检分析相关联。AIM2.MGluR5激动剂和拮抗剂对Poly I：C免疫攻击所致精神分裂症样症状的影响我们认为，药物阻断炎症反应将保护Poly I：C的炎症诱导的神经毒性效应。我们建议用特异性mGluR5拮抗剂(2-甲基-6-苯乙炔基)吡啶或正变构调节剂(3-cyano-N-(1，3-diphenyl-1H-pyrazol-5-yl)benzamide，CDPPB来阻断这一反应。实验程序与目标1相同。将对两个目标的数据集进行统计分析，以揭示药物的影响或炎症的程度和程度作为精神分裂症样病理的一个组成部分。意义：提出的研究将阐明免疫挑战动物模型中精神分裂症样症状的发病机制，并将允许测试这种疾病的神经发育概念中的治疗可能性，挑战精神分裂症的现有概念和治疗方法。 公共卫生意义：精神分裂症是一种慢性致残性疾病，影响着全球超过2%的人口，世界卫生组织因此将这种精神疾病确定为影响人类的十大最虚弱的疾病之一。精神分裂症是一种复杂的疾病，对其病因有几种理论，包括环境因素和炎症。在这个项目中，我们将研究代谢性谷氨酸受体功能是否表现出炎症依赖的调节，这有助于精神分裂症的发展，并将作为新的治疗靶点。

DESCRIPTION (provided by applicant): Schizophrenia is a multifactorial disease for which several theories have been postulated. It has also been hypothesized that a viral infection during pregnancy may alter or trigger improper fetal brain development. Indeed, prenatal injection of lipopolysaccharide or Poly I:C leads, in part, to sensorimotor gating deficits and locomotor sensitization to psychostimulant in rodent models later in life. These are two characteristics of schizophrenic patients. Interestingly, recent studies have demonstrated that the glutamatergic metabotropic receptor type 5 (mGluR5) is associated with disrupted sensorimotor gating response and altered psychostimulant-induced locomotor activity. mGluR5 is located both on neurons and glia. Variation in its expression could reflect functional changes of neuronal activity or participate in the inflammatory response, and serve as a new therapeutic target site. Aim 1. Investigation of the mGluR5 and inflammatory response in the poly I:C immune challenge animal model of schizophrenia. We hypothesize that the effects of Poly I:C will propagate a microglial activation and release of inflammatory mediators further aggravating the neuropathological conditions created by the toxin. Pregnant females mice at gestational day 9 will be injected with a dose of Poly I:C or saline. MicroPET imaging studies of inflammatory response using [11C]PK11195 and modulation of mGluR5 expression using [18F]FPEB, combined by behavioral studies, will be done at two time points (p35 (pre- puberty) and p80 (adulthood)) to relate the time course of inflammation to motor dysfunction and the extent of inflammatory response/modulation of mGluR5 function. Imaging will also be performed on pregnant females to assess these responses in the treated mothers and developing pups. End-point imaging studies will be correlated with post mortem analyses. Aim2. Investigation of the effect of mGluR5 agonist and antagonist on schizophrenia-like symptoms induced by poly I:C immune challenge. We propose that the pharmacological blockade of the inflammatory response will protect against inflammatory-induced neurotoxicity effects of Poly I:C. We propose to block this response with specific mGluR5 antagonist (2-methyl-6-(phenylethynyl)pyridine, MPEP) or positive allosteric modulator (3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide, CDPPB). Experimental procedures are identical to aim 1. Data sets of both aims will be statistically analyzed to reveal the effect of either drugs or the extent and magnitude of inflammation as a component of schizophrenia-like pathology. Significance: The studies proposed will shed light on the pathogenesis of schizophrenia-like symptoms in immune-challenge animal models, and will allow testing treatment possibilities in the neurodevelopmental concept of the disease, challenging the current concept and treatment approaches of schizophrenia. PUBLIC HEALTH RELEVANCE: Schizophrenia is a chronic and disabling disorder that affects more than 2 percent of population worldwide and the World Health Organization has thus identified this mental disease as one of the ten most debilitating diseases affecting human beings. Schizophrenia is a complex illness and there are several theories of its cause, including environmental factors and inflammation. In this project, we will investigate if metabotropic glutamate receptor function shows inflammation dependent modulation, which contributes to the development of schizophrenia and which would serve as a new therapeutic target site.