Targeting Glial mGluR5 in Schizophrenia

靶向神经胶质 mGluR5 治疗精神分裂症

• 批准号: 8100300
• 负责人: ANNA-LIISA BROWNELL
• 金额: $ 29.6万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100300
• 关键词: Abbreviations; Acoustics; Adult; Affect; Age; Agonist; Amphetamines; Animal Model; Animals; Autopsy; Behavior; Behavioral; Benzamides; Brain; Carbon; Characteristics; Chronic; Cognitive; Complex; Data; Data Analyses; Data Set; Development; Disease; Dose; Double-Stranded RNA; Embryo; Environmental Risk Factor; Female; Functional disorder; Gender; Glutamates; Human; Image; Immune; Immune response; Impairment; Inflammation; Inflammation Mediators; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Intravenous; Investigation; Isoquinolines; Label; Life; Light; Lipopolysaccharides; Measures; Metabotropic Glutamate Receptors; Modeling; Monitor; Mothers; Motor; Motor Activity; Mus; Nature; Neuroglia; Neurons; Pathogenesis; Pathology; Patients; Pharmaceutical Preparations; Phenotype; Poly I-C; Population; Positron-Emission Tomography; Pregnancy; Procedures; Psyche structure; Puberty; Reflex action; Rodent Model; Saline; Schizophrenia; Series; Short-Term Memory; Site; Social Interaction; Social Work; Symptoms; Testing; Time; Toxin; Variant; Virus Diseases; World Health Organization; base; behavior measurement; behavior test; benzonitrile; diphenyl; fetal; in utero; in vivo; intravenous injection; locomotor deficit; male; morris water maze; neurotoxicity; new therapeutic target; preadolescence; pregnant; prenatal; psychostimulant; public health relevance; pup; pyridine; receptor; receptor function; response; theories

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.

描述（由申请人提供）：精神分裂症是一种多因素疾病，对此已经提出了多种理论。还有假设称，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，产前注射脂多糖或多聚 I:C 在一定程度上会导致啮齿类动物模型在以后的生活中出现感觉运动门控缺陷和对精神兴奋剂的运动敏感性。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，5 型谷氨酸代谢受体 (mGluR5) 与感觉运动门控反应中断和精神兴奋剂引起的运动活动改变有关。 mGluR5 位于神经元和神经胶质细胞上。其表达的变化可以反映神经元活动的功能变化或参与炎症反应，并作为新的治疗靶点。目的 1. 研究精神分裂症多聚 I:C 免疫攻击动物模型中的 mGluR5 和炎症反应。我们假设 Poly I:C 的作用将促进小胶质细胞活化并释放炎症介质，进一步加剧毒素造成的神经病理状况。怀孕第 9 天的雌性小鼠将注射一定剂量的 Poly I:C 或盐水。使用 [11C]PK11195 进行炎症反应的 MicroPET 成像研究，使用 [18F]FPEB 调节 mGluR5 表达，结合行为研究，将在两个时间点（p35（青春期前）和 p80（成年期））进行，以将炎症到运动功能障碍的时间过程以及炎症反应/mGluR5 功能调节的程度。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。目标2。研究 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。我们认为，炎症反应的药理学阻断将防止 Poly I:C 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）。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，以揭示药物的效果或作为精神分裂症样病理学组成部分的炎症的程度和程度。意义：所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，并将允许测试该疾病的神经发育概念的治疗可能性，挑战当前的精神分裂症概念和治疗方法。 公共卫生相关性：精神分裂症是一种慢性致残性疾病，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使人衰弱的疾病之一。精神分裂症是一种复杂的疾病，其病因有多种理论，包括环境因素和炎症。在这个项目中，我们将研究代谢型谷氨酸受体功能是否表现出炎症依赖性调节，这有助于精神分裂症的发展，并将作为新的治疗靶点。