Inflammation Alters Histone Methylation in the Central Nervous System: Implications for Neuropsychiatric Disease: A Dissertation

Maternal infection during pregnancy is associated with increased risk of both schizophrenia and autism in offspring. Based on this observation, the maternal immune activation mouse model was developed, in which pregnant rodents are treated with immune-activating agents and the brains and behavior of the adult offspring studied. This model has been found to recapitulate a variety of molecular, cellular, and behavioral abnormalities observed in both schizophrenia and autism. However, despite the abundant evidence provided by these studies that prenatal exposure to inflammation alters brain development and function later in life, the molecular mechanisms by which inflammation mediates these effects remains unclear. It has been suggested that other prenatal risk factors for neuropsychiatric disease may alter brain development, in part, via epigenetic mechanisms such as DNA methylation and histone modification. However, a link between inflammation and epigenetic modification in brain has not been established. Therefore, the focus of my thesis was to examine the effect of inflammation on the histone modification, trimethylated histone H3 lysine 4 (H3K4me3), which has been implicated in both normal brain development and in schizophrenia. In Chapter II, I describe experiments examining the effect of a specific, cytokine, interleukin-6 (IL-6), on H3K4me3 in rat forebrain culture. I show that IL-6 treatment results in altered levels of H3K4me3 at multiple gene promoters, frequently in conjunction with altered mRNA expression levels, and demonstrate that a subset of these alterations appear to be dependent on signaling via the signal transducer and activator of transcription 3 (Stat3) pathway. Furthermore, some of the genes affected by IL-6 also showed altered H3K4me3 levels in autism postmortem brain. Though a direct link still remains to be established, this observation suggests that epigenetic changes observed in neuropsychiatric disease may have been induced by prenatal exposure to inflammation. In Chapter III, I describe in vivo experiments employing the maternal immune activation (MIA) mouse model to examine the effects of prenatal inflammation on H3K4me3 in the brain of the offspring, at both fetal and adult stages. I found that immune activation resulted in increased levels of IL-6 protein in fetal brain, working memory deficits in the adult offspring, and subtle changes in H3K4me3 levels in fetal and adult brain. Taken together, these findings demonstrate that an environmental risk factor for schizophrenia and autism—namely, inflammation—is capable of inducing robust and widespread histone modifications in a model of the central nervous system and smaller changes in vivo. This suggests that prenatal exposure to inflammation in human populations may lead to increased susceptibility for neuropsychiatric disorders, in part, by altering chromatin modifications in developing brain