Functional Role of IL-6 in Fetal Brain Development and Abnormal Behavior

母亲感染是一个环境因素，可能会增加子女患自闭症和精神分裂症的几率。在这种危险因素的动物模型中，怀孕小鼠的呼吸道感染产生的后代出现行为异常和神经病理，与自闭症和精神分裂症患者观察到的一致。这些变化可以通过母体注射dsRNA Poly(I：C)来模仿，这会引起抗病毒炎症反应。最近的研究表明，在这种母体免疫激活(MIA)模型中，细胞因子白介素6(IL-6)是必要和充分的，并且对于调节行为和转录变化是必要的。虽然IL-6对MIA的影响起着关键的调节作用，但IL-6改变神经发育的机制尚不清楚。我们最近证实，在MIA后不久，胎盘中母源的IL-6介导了胎盘中胎儿细胞的激活，并随后改变了重要内分泌因子的水平。然而，由于IL-6在MIA后也在胎儿大脑中上调，因此阐明IL-6在改变胎儿大脑发育中的作用机制是复杂的。本项目将研究IL-6在MIA子代异常行为发展中的作用途径。我们将确定胎盘和胚胎大脑中对MIA诱导的IL-6有反应并被其激活的细胞。我们将对携带IL-6RA-β-半乳糖苷酶转基因小鼠的IL-6RA启动子活性进行定位，以确定IL-6RA在胎儿大脑和胎盘中的表达。然后，我们将使用免疫组织化学方法检测IL-6RA激活的下游反应，包括转录因子STAT3和STAT1的磷酸化。重要的是，这个项目将精确定位IL-6对自闭症和精神分裂症内表型的发展至关重要的特定区域和细胞。我们将敲除IL-6R，特别是胎儿大脑和胎盘中的特定细胞类型和区域，并分析行为，以确定IL-6在哪里起作用，改变胎儿的大脑发育。长期目标是阐明IL-6导致与自闭症和精神分裂症相关的行为异常的分子机制。

Maternal infection is an environmental factor that can increase the incidence of autism and schizophrenia in the offspring. In an animal model of this risk factor, respiratory infection of pregnant mice yields offspring that develop behavioral abnormalities and neuropathology consistent with those observed in autistic and schizophrenic patients. These changes can be mimicked by maternal injection of the dsRNA, poly(I:C), which evokes an anti-viral inflammatory response. Recent studies have shown that the cytokine interleukin-6 (IL-6) is necessary and sufficient and necessary for mediating the development of behavioral and transcriptional changes in this maternal immune activation (MIA) model. While IL-6 is critical for mediating the effects of MIA, the mechanism by which IL-6 acts to alter neural development is unknown. We recently demonstrated that, shortly after MIA, maternally-derived IL-6 in the placenta mediates the activation of fetal cells in the placental, and subsequent changes levels of important endocrine factors. However, elucidating the mechanism of IL-6 action in altering fetal brain development is complicated by the fact that IL-6 is also upregulated in the fetal brain after MIA. This project will investigate the pathway of IL-6 action in mediating the development of abnormal behaviors in MIA offspring. We will identify the cells that are responsive to, and activated by, MIA-induced IL-6 in the placenta and embryonic brain. We will localize IL-6Ra promoter activity in mice carrying an IL-6Ra-beta-galactosidase transgene to determine where in the fetal brain and placenta IL-6Ra is expressed. We will then use immunohistochemical methods to detect downstream responses of IL-6Ra activation, including phosphorylation of the transcription factors, STAT3 and STAT1. Importantly, this project will pinpoint specific regions and cells for which IL-6 action is critical for the development of autistic and schizophrenic endophenotypes. We will knockout IL-6R in particular cell types and regions in the fetal brain and placenta and assay behavior to determine where IL-6 action acts to alter fetal brain development. The long-term goals are to elucidate the molecular mechanisms by which IL-6 causes behavioral abnormalities relevant for autism and schizophrenia.