Increased extracellular free-water in adult male rats following in utero exposure to maternal immune activation

Background: In previous work, we applied novel in vivo imaging methods to reveal that white matter pathology in patients with first-episode psychosis (FEP) is mainly characterized by excessive extracellular free-water, and to a lesser extent by cellular processes, such as demyelination. Here, we apply a back-translational approach to evaluate whether or not a rodent model of maternal immune activation (MIA) induces patterns of white matter pathology that we observed in patients with FEP. To this end, we examined free-water and tissue-specific white matter alterations in rats born to mothers exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (Poly-I:C) in pregnancy, which is widely used to produce alterations relevant to schizophrenia and is characterized by a robust neuroinflammatory response. Method: Pregnant dams were injected on gestational day 15 with the viral mimic Poly-I:C (4 mg/kg) or saline. Diffusion-weighted magnetic resonance images were acquired from 17 male offspring (9 Poly-I:C and 8 saline) on postnatal day 90, after the emergence of brain structural and behavioral abnormalities. The free-water fraction (FW) and tissue-specific fractional anisotropy (FA(T)), as well as conventional fractional anisotropy (FA) were computed across voxels traversing a white matter skeleton. Voxel-wise and whole-brain averaged white matter were tested for significant microstructural alterations in immune-challenged, relative to saline-exposed offspring. Results: Compared to saline-exposed offspring, those exposed to maternal Poly-I:C displayed increased extracellular FW averaged across voxels comprising a white matter skeleton (t(15) = 2.74; p = 0.01). Voxel-wise analysis ascribed these changes to white matter within the corpus callosum, external capsule and the striatum. In contrast, no significant between-group differences emerged for FA(T) or for conventional FA, measured across average and voxel-wise white matter. Conclusion: We identified excess FW across frontal white matter fibers of rats exposed to prenatal immune activation, analogous to our bedside observation in FEP patients. Findings from this initial experiment promote use of the MIA model to examine pathological pathways underlying FW alterations observed in patients with schizophrenia. Establishing these mechanisms has important implications for clinical studies, as free-water imaging reflects a feasible biomarker that has so far yielded consistent findings in the early stages of schizophrenia.