The effect of Interleukin-6 and maternal high fat diet on developmental gene expression in the embryonic mouse brain

Perturbations in the maternal environment during gestation can have serious health implications for the resulting child later in life. Maternal inflammation is one disruption to the maternal environment that is linked to several disease states in adult life. For example, in mice it has been shown that activation of the immune system and increased levels of the cytokines during gestation affects the development of brain areas involved in social interaction and memory, and results in a schizophrenia-like phenotype. In humans this finding is supported by epidemiological studies that demonstrate an association between maternal infection and the development of schizophrenia. Obesity is another disease state that may be caused by maternal inflammation. A correlation has been clearly shown in humans and rodent models between maternal obesity during pregnancy, and obesity in the offspring but the mechanism behind this is unknown. It has recently emerged that obesity is accompanied by a chronic state of low grade inflammation; obese individuals display significantly elevated levels of cytokines. Maternal inflammation could therefore mediate the predisposition of offspring to obesity later in life by affecting the development of brain areas that regulate body weight, just as perturbations may predispose children to schizophrenia. The hippocampus is one important brain region involved in social interaction and memory, and has been implicated in the development of schizophrenia. The arcuate nucleus is a different region that regulates bodyweight and it thus implicated in the development of obesity. We therefore hypothesised that elevated levels of maternal cytokines disrupt correct embryonic development of the hippocampus and arcuate nucleus by affecting the expression of key developmental genes, and that this disruption programs the increased risk of offspring for neurological disease later in life. The cytokine Interleukin-6 (IL-6) seems to be a major player in the prenatal programming of both these disorders so we initially used an in vitro model in which embryonic day 17.5 mouse brain was exposed to IL-6 at 100 ng/ml for 1 hour. The expression of genes encoding several developmentally important signalling molecules and their receptors were examined in the hippocampus and arcuate nucleus using quantitative PCR. These results were then replicated in vivo in the arcuate nucleus by creating a mouse model of maternal obesity. We found that in vitro IL-6 treatment altered the expression of the key neurodevelopmental genes Netrin1, Dcc, Sonic hedgehog and Gli1 in the embryonic hippocampus and/or arcuate nucleus. This implicates a possible mechanism by which prenatal IL-6 exposure disrupts the expression of important neurodevelopmental genes during embryogenesis, resulting in abnormal brain development and leading to an increased risk of neurological disease later in life. In addition to this we created a mouse model of maternal obesity. We then used this model to show that the same gene expression changes that occurred in the arcuate nucleus in response to in vitro IL-6 treatment also happen in vivo in response to maternal obesity. These data are key in establishing a mechanism to explain how increased IL-6 levels in maternal obesity are able to programme offspring to obesity. This research provides good evidence that fetal exposure to IL-6 during pregnancy changes the expression of important neurodevelopmental genes in the embryonic hippocampus and arcuate nucleus during prenatal development. Future research in this area has the potential to improve human health by creating a research-informed basis for human pregnancy health guidelines that will reduce the risk of these neurological disorders