The timing of prenatal immune challenge determines the extent of white matter microstructural anomalies relevant to autism

Abstract

BACKGROUND: Imaging and neuropathological studies point to the onset of pathology in neurodevelopmental disorders such as autism early in fetal life. 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 our clinical studies of autism, but direct evidence for a fetal trigger of these brain structural differences is sparse. Epidemiological studies implicate maternal inflammation during prenatal life as an environmental risk factor for autism in the offspring. OBJECTIVES: In this study we tested the hypothesis that maternal immune activation causes post-natal white matter microstructural anomalies in offspring relevant to schizophrenia or autism. We examined the effects of maternal inflammation in early and late gestation on white matter microstructure in the offspring using advanced small animal in-vivo MR-DTI. METHODS: We used an mouse model of maternal immune activation (MIA) by the viral mimic PolyI:C administered in early (day 9) or late (day 17) 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 of adult offspring. Region-of-interest manual tracing was used to confirm FA changes in selected white matter tracts. In addition we conducted a preliminary immunohistochemical exploration of the oligodendrocyte marker CNPase to determine whether myelination processes might contribute to any changes in FA observed. RESULTS: FA was lower in MIA exposed offspring throughout fronto-striatal-limbic circuits and in the corpus callosum. Regions with lower FA were more extensive in the early exposed group. In both groups there were regions with increased FA but again, these were more extensive in the early exposed group. Preliminary immunohistochemical evidence revealed reduction in the oligodendrocyte marker CNPase in mice exposed to MIA, consistent with a white matter structural insult affecting myelination CONCLUSIONS: The present results provide direct experimental evidence that prenatal inflammation causes white matter microstructural abnormalities analogous to those found in autism. Maternal inflammation earlier in gestation precipitates more extensive changes in offspring, suggesting that the fetus is more vulnerable to environmental insults early in development.