Maternal Immune Activation Perturbs Fetal Brain Development and Adult Behaviors Through Placental Trophoblast IL-6 Activation

Abstract

Background: Epidemiologic studies indicate maternal infection as a risk factor for autism and schizophrenia in the offspring. Maternal immune activation (MIA) in the dam, an animal model for maternal infection, leads the offspring exhibiting autistic- and schizophrenia-like behaviors. However, the mechanism of how MIA perturbs fetal brain development and precipitates the offspring behavior deficits and brain neuropathologies remains elusive. Prior works demonstrate maternal interleukin-6 (IL-6) is a key cytokine that mediates the effect of MIA on the offspring. Placenta as an interface between dam and fetus presumably plays a role in mediating the acute response to MIA in maternal-placental-fetal axis. Here, we are investigating the role of placental IL-6 activation in the etiology of MIA caused autistic and schizophrenia-like phenotypes. Methods: Induction of MIA is done by injecting viral mimic poly(I:C) into the dam at mid-gestation. The inflammatory responses in the fetal brain after poly(I:C) injection is examined to understand the impact of MIA to the brain development. To further investigate the role of placental IL-6 activation in MIA model, we specifically delete the receptor for IL-6, IL-6Ra, in the placenta of mice. By using placenta-specific IL-6Ra knockout mice, we are allowed to ask whether blocking placental IL-6 activation can prevent the acute inflammation in the placental-fetal axis and offspring behavioral abnormalities and neuropathologies. Results: We demonstrate MIA causes acute inflammatory responses in the fetal brain, including increased IL-6 expression and activated IL-6 downstream signaling in fetal prepontine and pontine hindbrain. The acute inflammatory response in the fetal brain following by MIA is found to depend on IL-6 level in the dam. Knockout of IL-6Ra in the placental trophoblast effectively blocks the inflammation in the placenta and ceases the inflammatory signaling in the fetal brain. Furthermore, the behavioral abnormalities and loss of cerebellar Purkinje cells seen in MIA offspring were successfully prevented by knockout IL-6Ra in the placental trophoblast. Conclusion: IL-6 activation in the placenta during maternal infection is indispensible for relaying the inflammatory signal from mother to fetal brain and impacting brain development and adult behaviors. Intervention of IL-6 activation in the placenta after infection could be a potential precaution for offspring developing autism and schizophrenia.

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