Journal
MOLECULAR PSYCHIATRY
Volume 25, Issue 5, Pages 1050-1067Publisher
SPRINGERNATURE
DOI: 10.1038/s41380-019-0604-0
Keywords
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Funding
- Advanced European Research Council [ERC-2016-ADG 741744]
- Israel Science Foundation-Legacy Heritage Biomedical Science Partnership-research [1354/15]
- Israel Science Foundation [991/16]
- Consolidated Anti-Aging Foundation Chicago
- Adelis Foundation
- Maurice and Ilse Katz Professorial Chair in Neuroimmunology
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Viral infection during pregnancy is often associated with neuropsychiatric conditions. In mice, exposure of pregnant dams to the viral mimetic poly(I:C), serves as a model that simulates such pathology in the offspring, through a process known as Maternal Immune Activation (MIA). To investigate the mechanism of such effect, we hypothesized that maternal upregulation of Type-I interferon (IFN-I), as part of the dam's antiviral response, might contribute to the damage imposed on the offspring. Using mRNA sequencing and flow cytometry analyses we found that poly(I:C) treatment during pregnancy caused reduced expression of genes related to proliferation and cell cycle in the offspring's microglia relative to controls. This was found to be associated with an IFN-I signature in the embryonic yolk sac, the origin of microglia in development. Neutralizing IFN-I signaling in dams attenuated the effect of MIA on the newborn's microglia, while systemic maternal administration of IFN beta was sufficient to mimic the effect of poly(I:C), and led to increased vulnerability of offspring's microglia to subsequent stress. Furthermore, maternal elevation of IFN beta resulted in behavioral manifestations reminiscent of neuropsychiatric disorders. In addition, by adopting a two-hit experimental paradigm, we show a higher sensitivity of the offspring to postnatal stress subsequent to the maternal IFN beta elevation, demonstrated by behavioral irregularities. Our results suggest that maternal upregulation of IFN-I, in response to MIA, interferes with the offspring's programmed microglial developmental cascade, increases their susceptibility to postnatal stress, and leads to behavioral abnormalities.
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