Neuroimmune Changes in Schizophrenia

描述(申请人提供)：妊娠中期母体感染和围产期缺氧是免疫系统和促炎细胞因子的有效激活剂，可能会影响正常的大脑发育，从而容易发展为精神分裂症。在我们最近对精神分裂症患者前额叶皮质的脑表达谱实验中，我们发现了一些与免疫反应相关的强劲基因表达变化。这些变化被qPCR证实，提示存在炎性细胞因子诱导的转录组特征，包括干扰素诱导的(IFITM家族)、MHC II类(DP、DR和DQ类)、热休克蛋白(HSP28和HSP70)、补体系统(C1和C3)和其他转录本。此外，到目前为止，几乎所有精神分裂症的高密度微阵列研究都报告了与免疫系统相关的表达变化。动物研究也支持精神分裂症的生物学变化与细胞因子表达之间的强烈联系。特别是，用单剂量合成细胞因子诱导剂多聚核苷-多核糖核酸[聚L：C]产前治疗大鼠或小鼠，会导致子代在青春期后出现中断的潜伏抑制、脉冲前抑制、多巴胺能机能亢进和脑病理。这表明病毒感染并不是必要的；母亲的免疫反应似乎是导致胎儿大脑发育变化的关键。基于这些发现，我们假设各种环境影响，通过促炎细胞因子的诱导，在发育中的大脑中触发强烈的转录组反应，这种反应可能会持续到成年。为了验证这一假设，我们将为小鼠和人设计全面的免疫定制DMA微阵列(目标1)，并分析30例精神分裂症患者和匹配对照组(目标2)的前额叶皮质(PFC)、颞上回(STG)和小脑(CBL)的免疫转录组。此外，我们将评估在不同时间点用聚(L：C)(目标3)处理的小鼠相应脑区的转录组变化。在确定了人类和小鼠数据集上共同的基因表达变化后(目标4)，我们将通过qPCR进行验证，并通过原位杂交定位最有希望的基因表达变化(目标5)。我们预测，精神分裂症患者将显示出直接受促炎细胞因子调节的特定免疫反应基因的持续变化，其中一些表达变化也将在胚胎期间暴露于聚(L：C)介导的细胞因子诱导的青少年/成年小鼠的大脑中观察到。这些普遍观察到的人类组织和小鼠模型(S)之间的免疫转录变化将帮助我们定义一个可测试的分子底物，环境影响通过该底物易患精神分裂症。

DESCRIPTION (provided by applicant): Second trimester maternal infection and perinatal hypoxia are potent activators of the immune system and pro-inflammatory cytokines, which may affect normal brain development, thus predisposing for developing schizophrenia. In our recent brain expression profiling experiments of the prefrontal cortex of subjects with schizophrenia, we have uncovered a number of robust gene expression changes related to the immune response. These changes, verified by qPCR, suggest an inflammatory cytokine-induced transcriptome signature that include interferon-inducible (IFITM family), MHC class II (DP, DR and DQ classes), heat-shock proteins (HSP28 and HSP70), complement system (C1 and C3) and other transcripts. In addition, virtually all high-density microarray studies of schizophrenia to date have reported expression changes related to the immune system. Animal studies also support a strong link between biological changes seen in schizophrenia and cytokine expression. In particular, prenatal treatment of rats or mice with a single dose of the synthetic cytokine inducer polyriboinosinic-polyribocytidilic acid [poly(l:C)] leads to postpubertal emergence of disrupted latent inhibition, prepulse inhibition (PPI), dopaminergic hyperfunction and brain pathology in the offspring. This suggests that viral infection is not necessary; the maternal immune response appears to be key in causing changes in fetal brain development. Based on these findings we hypothesize that various environmental influences, via pro-inflammatory cytokine induction, trigger a strong transcriptome response in the developing brain that may persist into adult life. To test this hypothesis, we will design comprehensive immune custom DMA microarrays for mouse and human (Aim 1) and analyze the immune transcriptome of prefrontal cortex (PFC), superior temporal gyrus (STG) and cerebellum (CBL) in 30 subjects with schizophrenia and matched controls (Aim 2). Furthermore, we will assess transcriptome changes in the corresponding brain regions of mice treated at various time points with poly(l:C) (Aim 3). After identification of the common gene expression changes across the human and mouse datasets (Aim 4) we will verify by qPCR and localize to cell type by in situ hybridization the most promising gene expression changes (Aim 5). We predict that subjects with schizophrenia will show consistently altered expression of specific immune response genes that are directly regulated by pro-inflammatory cytokines, and that some of these expression changes will also be observed in the brain of adolescent/adult mice that were exposed to poly(l:C)-mediated cytokine induction during embryonic life. These commonly observed immune transcript changes between the human tissue and mouse model(s) will help us define a testable molecular substrate by which environmental influences predispose for developing schizophrenia.