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.