Maternal Poly (I:C)-Induced Placental Inflammation and Endocrine Dysfunction Are Associated with Disrupted Corticogenesis in Mouse Offspring.

BACKGROUND/

OBJECTIVES

Maternal immune activation (MIA) increases the risk of Autism Spectrum Disorders (ASD). Experimental models demonstrate that maternal exposure to bacterial endotoxin or the viral mimic polyinosinic:polycytidylic acid [poly (I:C)] reliably recapitulates ASD-like behavioral abnormalities in offspring, yet the underlying neurobiological mechanisms linking MIA to altered neurodevelopment remain incompletely understood. Increasing evidence highlights the placenta as a critical mediator in shaping fetal brain development through immunological and hormonal regulation. Likewise, disruption of placental regulatory functions upon MIA may therefore represent a mechanistic pathway. Here, we investigated how alterations in placental cytokine profiles, innate immune cell composition, and endocrine outputs relate to neuroinflammation and neurogenesis in the offspring.

METHODS

Pregnant mice at gestational day 12.5 received a single intraperitoneal injection of poly (I:C). Placental macrophages, neutrophils, inflammatory cytokines, and nerve growth factor (NGF) expression were examined 72 h later. Neurodevelopmental outcomes, including microglial activity and neurogenic markers, were evaluated in mouse offspring at postnatal day (P) 1 and 6.

RESULTS

MIA induced a significant accumulation of monocytes and neutrophils in the placenta, which was associated with elevated levels of a broad spectrum of inflammatory mediators, including Th17-biased proinflammatory cytokines, chemokines, and adhesion proteins, in the placenta and amniotic fluid. In contrast, the placenta-derived NGF levels were significantly reduced. MIA induced strong and sustained microglial activation in the fetal and neonatal brain. This inflammatory milieu was accompanied by disrupted cortical neurogenesis, characterized by a marked increase in Ki67+ neuronal progenitor cells (NPCs) in the subventricular zone (SVZ), overproduction of early-born Tbr1+ neurons at P1, later-born Satb2+ neurons at P6.

CONCLUSIONS

Collectively, these findings suggest that heightened Th17 inflammatory signaling, coupled with impaired placental endocrine function, contributes to dysregulated cortical neurogenesis in the offspring.