Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia

描述(申请人提供)：青春期大脑发育障碍可能是精神分裂症(SZ)的基础。虽然许多报道表明SZ不存在星形胶质细胞增生症，但越来越多的证据表明，星形胶质细胞和小胶质细胞的功能改变以及异常的免疫/炎症反应也可能是SZ的基础。然而，目前还不清楚神经胶质细胞和炎症是否或在多大程度上参与了青春期大脑发育的变化。最近，我们发现SZ患者的活体神经细胞中免疫/应激相关基因的表达发生了变化。受影响最大的基因包括谷胱甘肽S转移酶thet2基因，它调节细胞解毒系统，保护细胞免受活性氧代谢产物的影响。氧化应激激活先天免疫信号，并在糖尿病、动脉粥样硬化和神经退行性疾病等各种疾病中促进炎症。事实上，我们观察到氧化应激增加了促炎细胞因子的表达。在这项拟议的研究中，我们将检验这一假设，即青春期胶质细胞激活和炎症反应有助于谷氨酸能突触的改变发育。我们将在体内下调GSTT2在小鼠特定发育阶段的表达，作为通过增加氧化应激诱导神经胶质细胞激活和炎症的模型。我们将表征击倒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。我们还将评估基因敲除对谷氨酸能突触发育和突触/树突状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。培训和研究提案将使候选人能够发展成为神经精神病学研究的独立研究员。该项目将有助于理解神经胶质细胞和炎症在青春期与SZ相关的大脑发育变化中的作用。 公共卫生相关性：尽管精神分裂症(SZ)患者存在胶质细胞功能障碍和免疫/炎症状态改变，但尚不清楚它们在SZ病理中的作用。在这项研究中，我们将表征神经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。利用我们最近的发现，SZ神经元对氧化应激具有内在的敏感性，我们将提供一个SZ相关神经元缺陷如何通过胶质细胞介导的炎症反应导致谷氨酸能突触发育改变的模型机制。这项研究将有助于进一步了解谷氨酸能突触发育的改变以及寻找新的治疗靶点(S)，使SZ的早期干预治疗成为可能。

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.