Role of Glia and Inflammation in Altered Synapse Development in Schizophrenia

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）的基础。虽然许多报告表明，星形胶质细胞增生是没有观察到SZ，越来越多的证据表明，改变功能的星形胶质细胞和小胶质细胞以及异常的免疫/炎症反应也可能是SZ的基础。尽管如此，目前还不清楚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改变。最近，我们发现免疫/应激相关基因的表达在SZ患者来源的活神经元细胞中发生改变。受影响最大的基因包括谷胱甘肽S-转移酶θ 2（GSTT 2）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。氧化应激激活先天免疫信号传导，并导致各种疾病如糖尿病、动脉粥样硬化和神经退行性疾病中的炎症。事实上，我们观察到氧化应激增加促炎细胞因子的表达。在拟议的研究中，我们将测试这一假设，即胶质细胞活化和炎症反应在青春期有助于改变发育的突触。我们将在小鼠的特定发育阶段进行GSTT 2表达的体内敲低，作为通过增加氧化应激诱导神经胶质细胞活化和炎症的模型。我们将描述敲除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。我们还将评估敲除对突触能突触发育和突触/树突免疫分子表达的影响。最后，我们将通过使用MyD 88的小胶质细胞特异性缺失来解决先天免疫信号传导在小胶质细胞中的作用，MyD 88是一种在先天免疫信号传导中起核心作用的分子。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调查员。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。

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.