Targeting Glial mGluR5 in Schizophrenia

描述（由申请人提供）：精神分裂症是一种多因素疾病，有几种理论已被假定。也有人假设，怀孕期间的病毒感染可能会改变或引发胎儿大脑发育不良。事实上，产前注射脂多糖或聚I：C导致，部分，感觉运动门控缺陷和运动敏化精神兴奋剂在啮齿动物模型在以后的生活。这是精神分裂症患者的两个特征。有趣的是，最近的研究表明，谷氨酸能代谢型受体5型（mGluR 5）与中断的感觉运动门控反应和改变精神兴奋剂诱导的运动活动。mGluR 5位于神经元和胶质细胞上。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，并可作为新的治疗靶点。目标1。精神分裂症poly I：C免疫攻击动物模型中mGluR 5和炎症反应的研究我们假设Poly I：C的作用将传播小胶质细胞活化和炎症介质的释放，进一步加重毒素引起的神经病理学状况。妊娠第9天的妊娠雌性小鼠将注射一定剂量的Poly I：C或生理盐水。将在两个时间点（p35（青春期前）和p80（成年期））进行使用[11 C] PK 11195的炎症反应和使用[18 F]FPEB的mGluR 5表达调节的MicroPET成像研究，并结合行为研究，以将炎症的时间过程与运动功能障碍和炎症反应/mGluR 5功能调节的程度联系起来。还将对妊娠雌性动物进行成像，以评估给药母体和发育中幼仔的这些反应。终点成像研究将与尸检分析相关。目标2。探讨mGluR 5激动剂和拮抗剂对poly I：C免疫攻击诱导的精神分裂症样症状的影响。我们认为炎症反应的药理学阻断将防止Poly I：C的炎症诱导的神经毒性作用。我们建议用特异性mGluR 5拮抗剂（2-甲基-6-（苯乙炔基）吡啶，MPEP）或正变构调节剂（3-氰基-N-（1，3-二苯基-1H-吡唑-5-基）苯甲酰胺，CDPPB）阻断这种反应。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，以揭示药物的作用或炎症的程度和程度作为精神分裂症样病理学的一个组成部分。重要性：提出的研究将阐明免疫激发动物模型中精神分裂症样症状的发病机制，并将允许在疾病的神经发育概念中测试治疗可能性，挑战精神分裂症的当前概念和治疗方法。 公共卫生相关性：精神分裂症是一种慢性和致残性疾病，影响全球2%以上的人口，因此世界卫生组织将这种精神疾病确定为影响人类的十大最衰弱疾病之一。精神分裂症是一种复杂的疾病，其原因有几种理论，包括环境因素和炎症。本课题旨在研究代谢型谷氨酸受体功能是否具有炎症依赖性调节作用，从而促进精神分裂症的发生发展，并为精神分裂症的治疗提供新的靶点。

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.