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。尽管许多报告显示SZ中未观察到星形胶质细胞形成，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。然而，目前尚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。受影响最大的基因包括谷胱甘肽s -转移酶2 （GSTT2）基因，该基因调节细胞解毒系统，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，并导致各种疾病的炎症，如糖尿病、动脉粥样硬化和神经退行性疾病。事实上，我们观察到氧化应激增加了促炎细胞因子的表达。在这项研究中，我们将验证青春期神经胶质细胞激活和炎症反应有助于改变谷氨酸突触发育的假设。我们将在小鼠的特定发育阶段对GSTT2的体内表达进行敲除，作为通过增加氧化应激诱导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谷氨酸突触发育和突触/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缺失MyD88来解决先天免疫信号在小胶质细胞中的作用，MyD88是一个在先天免疫信号中起核心作用的分子。培训和研究计划将使候选人发展成为神经精神病学研究的独立研究者。该项目将有助于理解神经胶质细胞和炎症在青春期与SZ相关的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.