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

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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.