Description
Maternal immune activation reduces microglia proliferation in the developing brain via type-I interferon-dependent mechanism
H. Ben-Yehuda1, O. Matcovitch-Natan1,2, A. Kertser1, A. Spinrad1,2, I. Amit2 and M. Schwartz1.
1Department of Neurobiology and 2Department of Immunology, Weizmann Institute of Science, 7610001 Rehovot, Israel
Neurodevelopmental diseases are often associated with viral infection during pregnancy. In mice, Maternal Immune Activation (MIA) results in cognitive and social abnormalities of the offspring at adulthood. However, the underlying mechanism is still not fully understood. Here we hypothesized that prenatal immune challenge might impact the developing microglia in a type-I interferon-dependent manner. To test this hypothesis, we treated pregnant dams with the viral mimetic poly(I:C), a TLR3 ligand, as the prenatal inflammatory stimuli, 14.5 days following gestation, and compared the microglia isolated from their offspring to microglia isolated from offspring of PBS treated pregnant controls. Using high-throughput mRNA sequencing and gene ontology analyses, we found a reduction in expression of genes related to proliferation and cell cycle in the microglia isolated from newborn offspring of poly(I:C) injected dams. The reduction of proliferation was confirmed by flow cytometry analysis, assessing microglial expression of the proliferation marker Ki67. Moreover, RTqPCR examination of embryonic yolk sac, the origin of microglia in the developing offspring, following the maternal poly(I:C) treatment, showed a signature of genes related to type-I interferon, compared to control samples. Blocking maternal interferon type-I signaling by systemic administration of antibody directed against interferon receptor-1, one day prior to the MIA, prevented some of the effect of MIA on the newborn microglia. Furthermore, systemic treatment of pregnant dams with IFNβ, led to a reduction in expression of Ki67 relative to control samples, which recapitulates to some extent the MIA. Moreover, maternal separation of IFNβ pups, led to a higher activation of their microglia, as compared to controls. Our results suggest that immune activation during pregnancy upregulates maternal interferon type-I that in turn interferes with the microglia programmed development cascade, which could impact neurodevelopmental phenotype at adulthood.