Prenatal immune challenge as a risk factor for white matter microstructural anomalies relevant to schizophrenia

Abstract

SUMMARY: Epidemiological studies have reached a general consensus that maternal infection increases the risk of schizophrenia in the offspring. Schizophrenia is postulated to be disconnection syndromes involving white matter abnormalities. In present study we used advanced in-vivo Diffusion Tensor Imaging methods to quantify changes in white matter microstructure precipitated by prenatal immune challenge in early pregnancy. We report evidence for an impact of maternal immune exposure on white matter indices which may hold clues to the underlying mechanisms involved in schizophrenia. INTRODUCTION: Imaging and neuropathological studies point to the onset of pathology in neurodevelopmental disorders such as autism and schizophrenia as early in fetal life. In both conditions white matter connections appear to be disrupted, leading to altered functional connectivity during higher-order cognitive processing. We have previously reported diffusion tensor imaging (DTI) evidence of microstructural pathology in schizophrenia in our clinical studies, but direct evidence for a fetal trigger of these later brain structural differences is sparse. Epidemiological studies implicate maternal infection during prenatal life as a strong risk factor for schizophrenia in the offspring therefore we tested the hypothesis that maternal immune activation causes post-natal white matter microstructural anomalies in offspring relevant to schizophrenia. MATERIALS AND METHODS: We used a mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) gestation. A novel application of automated voxel-based morphometry (VBM) of in-vivo MRI data mapped fractional anisotropy (FA, directional diffusion of water) across white matter pathways. Region-of-interest (ROI) manual tracing was used to confirm FA changes in selected white matter tracts. CNPase (2,3-cyclic nucleotide 3-phosophodiestase) was used as oligodendrocyte marker to explore possible neuropathological mechanisms underlying morphological changes. RESULTS: FA indices were decreased in fimbria (fi), cerebal peduncle (cpd), external capsule (ec) and in the corpus callosum (cc) in adult mice exposed to maternal immune activation on GD9. Besides, FA indices were increased in cerebral cortex (CTX) in adult offspings exposed to PolyI:C immune challenge on GD9. ROI confirmed FA change in external capsule. Concomitant changes were found with CNPase using immunohistochemistry. CONCLUSION: The prenatal immune challenge has an impact on white matter changes in major neural pathways. The present results suggest that prenatal infection may indeed play a role in the brain dysconnectivity abnormalities associated with schizophrenia.