Toll-like Receptor-Selective Placental Vulnerability, Fetal Brain Impairment, and Post-Natal Behavioral Deficits in Mouse Models of Neurodevelopmental Disorder
Neurodevelopmental disorders (NDD), such as autism and schizophrenia have a diverse and multi-faceted etiology that is poorly understood, though epidemiological studies suggest that environmental risks such as prenatal infections or other gestational immune events correlate with increased NDD risk. Innate immune responses are evoked by toll-like receptor (TLR)-dependent signaling pathways. Both bacterial- (TLR4-selective) and viral- (TLR3-selective) mimetic-mediated maternal immune challenges have been shown to result in brain and behavioral changes (as reviewed by Meyer 2014), however, differences in methodologies prevent the direct comparison of the TLR-selective effects.
Previously, we demonstrated that a TLR4-selective insult at embryonic day 12.5 (E12.5) has adverse effects on fetal and placental health, proliferation of radial glial cells, altered cortical laminar patterning in the adult and behavioral deficits (Carpentier et. al 2013). Here, we aim to directly determine the differential effects of TLR3- and TLR4-selective agonists on a similar set of assays.
Pregnant mice were challenged with a TLR3- or TLR4-selective insult on E12.5 and placental pathology and pregnancy outcomes were evaluated by quantifying tissue necrosis and fetal survival, respectively. Neocortical alterations in the developing fetuses were examined via immunohistochemistry for markers of cell proliferation and neural progenitor cell populations. Finally, behavioral outcomes were measured using tasks that evaluate behaviors analogous to the symptoms of NDDs, including pup ultrasonic vocalizations, juvenile play, social approach, and pre-pulse inhibition.
Our results indicate that bacterial and viral immune insults differentially affect placental health, fetal viability and early embryonic brain development. Post-natal behavioral outcomes also appear divergent with the TLR3-mediated insult leading to a more pronounced behavioral phenotype in the offspring.
These findings suggest that specific immune events create differential outcomes for the health of the placenta and fetus and lead to distinct changes in cortical patterning which can ultimately manifest as unique behavioral symptoms. Our results have implications for understanding how similar environmental insults may lead to distinct developmental disorders or contribute to the heterogeneity of a specific condition.