PRENATAL TLR3 AND TLR7/8 ACTIVATION DISRUPTS EARLY CA3 PYRAMIDAL CELLS’ EXCITABILITY

Prenatal stress mediated by maternal immune activation (PS-MIA) is a risk factor for the development of psychiatric disorders in offspring. This transient condition triggers long-term changes in synaptic strength and plasticity of hippocampal neurons. Despite the growing number of studies examining PS-MIA alterations, its effects during the early postnatal development (P3-P6) have not yet been investigated. During early development, depolarizing GABAergic potentials at the mossy fiber-CA3 pyramidal cell synapse play a critical role in hippocampal network maturation. Therefore, this study examined whether PS-MIA alters the expression of the chloride transporter KCC2 and the occurrence of GABA-mediated giant depolarizations in offspring during postnatal days P3-P6. PS-MIA was induced with poly I:C (4 mg/kg, i.p.) or resiquimod (RQ, 2 mg/kg, i.p.) to activate TLR3 or TLR7/8 innate immunity receptors, respectively, and patch-clamp experiments on acute slices were performed in the dorsal hippocampus. Flow cytometry on maternal plasma and fetal brain tissue confirmed differential cytokine production in response to PS-MIA mediated by Poly I:C or RQ. Electrophysiological recordings revealed significant changes in the passive electrophysiological properties and a marked reduction in the excitability of CA3 pyramidal cells and local interneurons. Interestingly, these effects were TLR agonist-specific, indicating that Poly I:C and RQ activate distinct signaling cascades. Consistent with these alterations, GABA-mediated giant depolarizations exhibited increased frequency and amplitude in RQ-mediated PS-MIA slices. Our findings suggest that PS-MIA engages distinct innate immune pathways that modify hippocampal excitability, providing mechanistic insight into circuit vulnerability relevant to psychiatric disorders.