Prenatal exposure of mice to a maternal immune challenge leads to neurobiological changes in offspring relevant to schizophrenia

Abstract

Maternal infection during pregnancy increases the risk of serious neuropsychiatric disorders, such as schizophrenia and autism, in the offspring. MRI in patient populations shows white matter abnormalities and postmortem microarray and qPCR studies in the literature point to gene expression alterations in oligodendrocytes. We hypothesized that viral infection during pregnancy is an environmental risk factor for both the altered expression of genes regulating white matter development and subsequent ventricular enlargement in offspring. We used a mouse model of maternal immune activation (MIA) by the viral mimic poly(I : C) administered in early (day 9) or late (day 17) gestation. Automated voxel-based morphometry (VBM) of in vivo MRI data mapped cerebrospinal fluid across the whole brain. Manual region-of-interest tracing of lateral ventricles confirmed close overlap in ventricular volumes extracted by each technique (Dice coefficient = 0.93). We evaluated the behavioral and pharmacological impact of the prenatal exposure by using the prepulse inhibition paradigm and an amphetamine challenge in the same mice. Gene expression patterns of several white matter markers were characterized by in situ hybridization and immunohistochemistry. Maternal immune activation, in early but not late gestation, caused significant enlargement of lateral ventricles in adulthood. This early exposure disrupted prepulse inhibition and enhanced amphetamine sensitivity. Immune challenge in late gestation caused significant expansion of fourth-ventricle volume and a lesser degree of amphetamine potentiation.