Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia

神经胶质细胞和炎症在精神分裂症突触发育改变中的作用

• 批准号: 8091057
• 负责人: Shinichi Kano
• 金额: $ 7.22万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-22 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8091057
• 关键词: Address; Adolescence; Adult; Affect; Astrocytes; Atherosclerosis; Autoimmune Diseases; Biochemical; Brain; CD3 Antigens; Cells; Complement; Complement 1q; Data; Defect; Development; Diabetes Mellitus; Disease; Drug Metabolic Detoxication; Early treatment; Enzyme-Linked Immunosorbent Assay; Functional disorder; Gene Expression; Genes; Genetic Predisposition to Disease; Glutamates; Glutathione S-Transferase; Goals; Immune; Immunohistochemistry; Infection; Inflammation; Inflammatory; Inflammatory Response; Injection of therapeutic agent; Injury; Lead; Life; Mediating; Mediator of activation protein; Microglia; Modeling; Mus; Mutant Strains Mice; MyD88 protein; Myelogenous; Neurodegenerative Disorders; Neuroglia; Neuronal Dysfunction; Neurons; Oxidative Stress; Oxygen; Pathology; Patients; Play; Predisposition; Production; RNA Interference; Reporting; Research; Research Personnel; Research Proposals; Reverse Transcriptase Polymerase Chain Reaction; Role; Schizophrenia; Signal Transduction; Staging; Stress; Subfamily lentivirinae; Synapses; System; Testing; Time; Training; Virus; astrogliosis; cytokine; frontal lobe; glial cell development; hippocampal pyramidal neuron; in vivo; knock-down; neuropsychiatry; new therapeutic target; postnatal

DESCRIPTION (provided by applicant): Disturbance in brain development during adolescence may underlie schizophrenia (SZ). Although many reports showed that astrogliosis is not observed in SZ, accumulating evidence suggests that altered function of astrocytes and microglia as well as aberrant immune/inflammatory responses may also underlie SZ. Nonetheless, it is unclear whether or to what extent glial cells and inflammation are involved in altered brain development during adolescence. Recently, we have found that the expression of immune/stress related genes is altered in live neuronal cells derived from SZ patients. The most affected genes include glutathione S-transferase theta 2 (GSTT2) gene, which regulates cellular detoxification system and protects cells from reactive oxygen metabolites. Oxidative stress activates innate immune signaling and contributes to inflammation in various diseases such as diabetes, atherosclerosis, and neurodegenerative disorders. Indeed, we observed increased expression of proinflammatory cytokines by oxidative stress. In the proposed study, we will test the hypothesis that glial cell activation and inflammatory responses during adolescence contribute to altered development of glutamatergic synapses. We will perform in vivo knockdown of GSTT2 expression at specific developmental stages in mice as a model to induce glial cell activation and inflammation via increased oxidative stress. We will characterize the effects of knockdown on the activation of microglia and astrocytes as well as the production of proinflammatory cytokines. We will also assess the effects of knockdown on development of glutamatergic synapses and the expression of synaptic/dendritic immune molecules. Finally, we will address the role of innate immune signaling in microglia by using microglia-specific deletion of MyD88, a molecule that plays a central role in innate immune signaling. The training and research proposal will enable the candidate to develop into an independent investigator in neuropsychiatry research. The project will contribute to the understanding of the roles for glial cells and inflammation in altered brain development during adolescence relevant to SZ. PUBLIC HEALTH RELEVANCE: Although glial cell dysfunction and altered immune/inflammatory status have been suggested in patients with schizophrenia (SZ), it is not clear how they contribute to the pathology of SZ. In this study, we will characterize the role of glial cell activation and inflammatory response in altered brain maturation during adolescence. By utilizing our recent findings that SZ neurons have intrinsic susceptibility to oxidative stress, we will provide a model mechanism how SZ-associated neuronal defects lead to altered development of glutamatergic synapses via glia-mediated inflammatory responses. The study will contribute to the further understanding of altered development of glutamatergic synapses as well as identification of novel therapeutic target(s) that enables early intervention treatment for SZ.

描述（由申请人提供）：青春期大脑发育障碍可能是精神分裂症（SZ）的根源。尽管许多报告表明星形胶质细胞增生在 SZ 中并未观察到，但越来越多的证据表明星形胶质细胞和小胶质细胞功能的改变以及异常的免疫/炎症反应也可能是 SZ 的基础。尽管如此，目前尚不清楚神经胶质细胞和炎症是否或在多大程度上参与青春期大脑发育的改变。最近，我们发现来自 SZ 患者的活神经元细胞中免疫/应激相关基因的表达发生了改变。受影响最严重的基因包括谷胱甘肽 S-转移酶 theta 2 (GSTT2) 基因，该基因调节细胞解毒系统并保护细胞免受活性氧代谢物的影响。氧化应激会激活先天免疫信号，并导致糖尿病、动脉粥样硬化和神经退行性疾病等多种疾病的炎症。事实上，我们观察到氧化应激导致促炎细胞因子的表达增加。在拟议的研究中，我们将测试青春期期间胶质细胞激活和炎症反应导致谷氨酸突触发育改变的假设。我们将在小鼠特定发育阶段体内敲低 GSTT2 表达，作为模型，通过增加氧化应激诱导神经胶质细胞活化和炎症。我们将描述敲低对小胶质细胞和星形胶质细胞的激活以及促炎细胞因子的产生的影响。我们还将评估敲低对谷氨酸能突触发育和突触/树突免疫分子表达的影响。最后，我们将通过小胶质细胞特异性删除 MyD88 来解决先天免疫信号在小胶质细胞中的作用，MyD88 是一种在先天免疫信号中发挥核心作用的分子。培训和研究计划将使候选人能够发展成为神经精神病学研究的独立研究者。该项目将有助于了解神经胶质细胞和炎症在与 SZ 相关的青春期大脑发育改变中的作用。 公共健康相关性：尽管精神分裂症 (SZ) 患者存在神经胶质细胞功能障碍和免疫/炎症状态改变，但尚不清楚它们如何影响 SZ 的病理学。在这项研究中，我们将描述胶质细胞激活和炎症反应在青春期大脑成熟改变中的作用。通过利用我们最近的发现，即 SZ 神经元对氧化应激具有内在敏感性，我们将提供一个模型机制，SZ 相关神经元缺陷如何通过神经胶质介导的炎症反应导致谷氨酸突触发育改变。该研究将有助于进一步了解谷氨酸能突触发育的改变，以及识别新的治疗靶点，从而实现 SZ 的早期干预治疗。