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，已有几种理论假设。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，在啮齿动物模型中，产前注射脂多糖或聚I:C在一定程度上导致了感觉运动门控缺陷和对精神兴奋剂的运动敏感。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，谷氨酸代谢受体5型（mGluR5）与感觉运动门控反应中断和精神兴奋剂诱导的运动活动改变有关。mGluR5位于神经元和胶质细胞上。其表达的变化可反映神经元活性的功能变化或参与炎症反应，可作为新的治疗靶点。目的1。精神分裂症poly I:C免疫攻击动物模型中mGluR5与炎症反应的研究。我们假设Poly I:C的作用将传播小胶质细胞的激活和炎症介质的释放，进一步加重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Poly I:C或生理盐水。使用[11C]PK11195和[18F]FPEB调节mGluR5表达进行炎症反应的微pet成像研究，结合行为研究，将在两个时间点（p35（青春期前）和p80（成年））进行，以将炎症的时间过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。还将对怀孕的母鼠进行成像，以评估接受治疗的母鼠和发育中的幼崽的这些反应。终点成像研究将与死后分析相关联。Aim2。mGluR5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提出炎症反应的药理学阻断将保护Poly I:C免受炎症诱导的神经毒性作用。我们建议用特异性mGluR5拮抗剂（2-甲基-6-（苯乙基）吡啶，MPEP）或正变构调节剂（3-氰- n -（1,3-二苯基- 1h -吡唑-5-基）苯酰胺，CDPPB）阻断这种反应。实验步骤与目的1相同。这两个目标的数据集将进行统计分析，以揭示药物的作用或炎症作为精神分裂症样病理组成部分的程度和程度。意义：提出的研究将揭示免疫挑战动物模型中精神分裂症样症状的发病机制，并将允许在疾病的神经发育概念中测试治疗可能性，挑战当前精神分裂症的概念和治疗方法。

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.