Prenatal immune challenge compromises the normal course of neurogenesis during development of the mouse cerebral cortex

Abstract

Maternal infection during pregnancy is an environmental risk factor for the development of severe brain disorders in offspring, including schizophrenia and autism. However, little is known about the neurodevelopmental mechanisms underlying the association between prenatal exposure to infection and the emergence of cognitive and behavioral dysfunctions in later life. By injecting viral mimetic polyriboinosinic-polyribocytidylic acid (Poly I:C) into mice, we investigated the influence of maternal immune challenge during pregnancy on the development of the cerebral cortex of offspring. Our previous study showed that stimulation of the maternal immune system compromised the expression properties of transcription factors and the synaptogenesis of cortical neurons in upper layers but not those in deeper layers. The objective of the current study was to examine further whether maternal immune challenge has an influence on the cellular-biological features of the cortical progenitors that generate distinct cortical neuronal subtypes. We found the following abnormalities in the cortex of mice given the prenatal Poly I:C injection during later stages of cortical neurogenesis. First, proliferative activity and the expression of Pax6, which is a master regulator of the gene expression of transcription factors, were significantly decreased in the cortical progenitors. Second, the laminar allocation and gene expression were significantly altered in the daughter neurons generated at the same birth dates. These results demonstrate that specific abnormalities in the cortical progenitors preceded deficits in neuronal phenotypes. These changes may underlie the emergence of psychiatric brain and behavioral dysfunctions after in utero exposure to an infection.

Autism spectrum disorder: neuropathology and animal models

“…MIA mice are induced by influenza-infection or synthetic double-stranded RNA (poly I:C), as a mimic of viral infection in dams. MIA mice have delayed cell development in the neocortex [333] and reduced cell density and abnormal developmental migration in the cerebellum [325]. The offspring of pregnant rhesus monkeys treated with poly I:C have thinner apical dendrites with more proximal dendritic branching in the dorsolateral prefrontal cortex [383].…”

Prenatal Infection Affects the Neuronal Architecture and Cognitive Function in Adult Mice

“…; Sigma, St. Louis, Mo., USA) or saline at gestational day 9.5, which corresponds approximately to the first trimester of a human pregnancy. The dose and timing of the poly I:C treatment were based on previous studies [13]. After weaning (postnatal day 30, PD30), the mice were group-housed (3-5) in the Laboratory Animal Center of the College of Medicine, National Taiwan University, under a 12:12 light-dark cycle with free access to food and water.…”

Altered Postnatal Cell Proliferation in Brains of Mouse Pups Prenatally Exposed to IgG from Mothers of Children with Autistic Disorder

“…Previously reported findings of the age dependence of MCAD auto antibodies reactivity in rat brains,20 where patterns of reactivity were detected to prenatal (gestational day 18), but not on postnatal (day 8) or in adult rat brain proteins, make these new findings of significant postnatal alterations in cell proliferation from prenatal IgG exposure salient. The evidence that only gestational exposure dictates reactivity in fetal brain and that exposure results in long-term effects on brain development postnatally may be of importance in understanding the mechanisms underlying the pathophysiology 21,22…”