Fetal innate immunity contributes to the induction of atypical behaviors in a mouse model of maternal immune activation

Abstract

SummaryMaternal immune activation (MIA) increases likelihood of altered neurodevelopmental outcomes. Maternal cytokines are proposed to affect fetal brain development in mice; however, the contribution of fetal immunity to neurodevelopmental disorders is largely unexplored. Here, we show that MIA mediated by Toll-like receptor 3 (TLR3), but not other TLRs, induces a specific set of behavioral phenotypes including decreased sociability and increased restricted repetitive behavior in offspring. Accordingly, these behavioral phenotypes were absent when offspring were deficient for Trif, the downstream adapter molecule of TLR3. Using single-cell RNA sequencing, we identified clusters of border-associated macrophages that were significantly enriched in the fetal brain following TLR3-MIA, and these clusters were diminished in Trif−/− fetal brains.Moreover, we found that triggering TLR3-TRIF in offspring can occur through transplacental viral infection, resulting in altered behavioral phenotypes. Collectively, our data indicate that fetal innate immunity contributes to MIA-induced atypical behaviors in mice.

Estrogen Receptor β as a Candidate Regulator of Sex Differences in the Maternal Immune Activation Model of ASD

“…Indeed, MIA induces an adaptive immune response in mothers, particularly the activation of a subset of T helper cells (Th17 T cells) and the release of maternal cytokines such as interleukin (IL)-17, that can affect fetal brain development in mice ( Choi et al, 2016 ). However, a few groups, including ours, have reported that MIA may also directly induce an inflammatory innate immune response in fetal myeloid cells ( Onore et al, 2014 ; Matcovitch-Natan et al, 2016 ; Carlezon et al, 2019 ; Ben-Yehuda et al, 2020 ; Cui et al, 2020 ; Nichols et al, 2020 , preprint).…”

“…This MIA-induced ASD model displays behavioral phenotypes, including decreased sociability, increased repetitive restricted behavior, impaired learning and memory, altered levels of anxiety, and hyperactivity ( Patterson, 2011 ; Estes and McAllister, 2016 ). Importantly, several groups have reported that the behavioral phenotypes in this model are only observed in male offspring ( Xuan and Hampson, 2014 ; Coiro and Pollak, 2019 ; Haida et al, 2019 ; Keever et al, 2020 ; Nichols et al, 2020 , preprint; Figure 1A ). Based on these findings, MIA induction in mice is widely used to study the mechanism of ASD because it successfully recaptures behavioral phenotypes and sex-specific features observed in the disorder.…”

“…Although the precise mechanism is not clear, a recent publication indicates that MIA-activated BAMs in the choroid plexus secrete the chemokine CCL2 into the fetal ventricle, resulting in enhanced local inflammation ( Cui et al, 2020 ). Moreover, our single-cell RNA-sequencing (scRNA-seq) analysis showed that the activation of fetal BAMs in response to MIA was dependent upon fetal Trif , an essential signaling molecule downstream of TLR3 ( Nichols et al, 2020 , preprint). These findings indicate that MIA leads to fetal innate immune signaling in BAMs.…”