Maternal immune activation alters the behavioral, cytokine, and gene expression profiles in rat offspring

Maternal immune activation (MIA) is a risk factor for the development of schizophrenia and autism. The relationship between maternal infection and atypical fetal development is likely mediated by the activation of the maternal immune system, notably with elevated inflammatory cytokines in the fetal environment, but the intervening cellular and molecular links between infection and risk for neuropsychiatric disorders are unknown. The following dissertation addressed the behavioral, immunological, and molecular effects of MIA in the offspring of pregnant Sprague-Dawley rats given an intraperitoneal (0.25 mg/kg) injection of lipopolysaccharide (LPS) on embryonic day 15.;In Study 1, the consequences of maternal LPS on postnatal behavioral development were examined. Offspring born to LPS-dams exhibited reduced social preference and exploration behaviors as juveniles and adults. In Study 2, the effects of maternal LPS on cytokine, chemokine, and growth factor protein levels in maternal serum, amniotic fluid, and fetal brain at 4 and 24 h post injection were examined. Across the three compartments, LPS elevated pro-inflammatory cytokine and chemokine levels at 4 h, and levels decreased but remained elevated at 24 h. The greatest elevations were in serum, followed by amniotic fluid, then fetal brain. Treatment initially reduced anti-inflammatory cytokine levels at 4 h, which could partly explain the sustained cytokine response. Growth factor levels in the fetal brain were reduced at both time points. Study 2 could not address the source of inflammatory proteins in the fetal brain, but based on the failure to detect cytokine mRNA induction by microarray and quantitative real-time PCR performed in Study 3, the fetal brain cytokines are likely to be derived from maternal fluids or placenta. Study 3 was designed to elucidate the possible molecular mechanisms by which maternal LPS affects the fetal brain. Microarray analysis of mRNA expression levels in the whole fetal brain 4 h post maternal LPS injection revealed a significant up-regulation of hypoxia and cellular stress-responding genes and selective down-regulation of neurodevelopmental genes, specifically those that regulate neuronal migration. Genes controlling migration of gamma-amino butyric acid (GABA)ergic interneurons were specifically affected. These results offer a novel mechanism by which MIA can disrupt fetal CNS development.