Nicotinic Cholinergic Modulation of the Fetal Brain Response to Maternal Immune Activation

Background: Mutation of human chromosome 15q13.3 increases the risk for autism and schizophrenia. One of the noteworthy genes in 15q13.3 is CHRNA 7, which encodes the nicotinic acetylcholine receptor alpha 7 subunit (α7nAC hR) associated with schizophrenia in clinical studies and rodent models. This study investigated the role of α7nAC hR in maternal immune activation (MIA) mice model, a murine model of environmental risk factor for autism and schizophrenia. Methods: We provided choline, a selective α7nAC hR agonist, in the diet of C57BL/6 wild-type dams throughout gestation and the lactation period and induced MIA at mid-gestation. The adult offspring behavior and gene expression profile in the maternal splenic-placenta-fetal brain axis at midgestation were investigated. Results: We found that the choline supplementation prevented several MIA behavioral abnormalities in the wild-type offspring. Pro-inflammatory cytokine IL-6 and Chrna7 gene expression in the wild-type fetal brain were elevated by poly(I:C) injection and were suppressed by gestational choline supplementation. We further investigated the gene expression level of IL-6 in Chrna7 mutant mice. We found the basal level of IL-6 gene expression was higher in Chrna7 mutant fetal brain, which suggests that α7nAC hR may serve an anti-inflammatory role in the fetal brain during development. Lastly, we induced MIA in Chrna7+/-offspring and tested for their behavior. The Chrna7+/- offspring were more vulnerable to MIA, showing several behavioral abnormalities. Conclusion: Our study shows that the α7nAC hR modulates the inflammatory response in the fetal brain and offspring behavior development after maternal infection.