Toll-like Receptor-Selective Placental Vulnerability in an Autism Mouse Model
Objectives: Our objective is to determine if TLR selective responses have distinct effects on fetal-maternal interaction during early pregnancy in the mouse. Our recent studies suggest that TLR4 activation leads to cortical patterning defects in adult offspring born from maternal immune activation (MIA)-challenged pregnant mothers (Carpentier et al. 2013). We hypothesized that placental pathogenesis evoked by TLR4 activation may selectively alter fetal brain development through hypoxia-related mechanisms while the activation of other TLRs may not.
Methods: Pregnant mice were challenged with different TLR agonists at embryonic day 12.5 (E12.5) during mid-gestation and we analyzed the pregnancy outcomes and fetal brain phenotypes. After systemic prenatal insults such as bacterial (TLR4) and viral (TLR3) infection-mediated MIA responses, we examined placental pathology and neocortical alterations in the developing fetuses, including neural progenitor cell proliferation, cell cycle alterations, and stem cell niche signaling molecules in TLR-challenged animals compared with saline-injected control animals.
Results: Activation of different TLRs led to distinct alterations in placental pathology and fetal growth in early development. The cryoarchitecture of the developing cerebral cortex was severely affected by several specific TLR challenges with unique immune cytokine profiles. Proliferation and divisions of neural progenitor cells were impaired by prenatal insults with specific TLR activation. Acute effects on neurodevelopmental processes were pronounced in TLR4-challenged animals suggesting significantly higher risk of neuropathology from bacterial infections during pregnancy than for other classes of immunogen.
Conclusions: Our data suggests that alterations in early cortical development may be distinct for each class of maternal immune response. Therefore, despite the behavioral similarities of adult animals, there are significant differences in the severity and the type of defects in cortical patterns induced by each TLR-dependent pathway. The data indicate that various TLR pathways may contribute unique immune-related alterations in the fetal-maternal interface and in early brain development.