Matteo Bizzotto, Shih Feng You, Matteo Tamborini, Elisa Faggiani, Raffaella Morini, Antonella Borreca, Rui Zhang, Ekaterina Aladyeva, Aasritha Nallapu, Claudio Ferrari, Oscar Harari, Davide Pozzi, Ricardo D'Oliveira Albanus, Celeste M. Karch, Michela Matteoli, Fabia Filipello
Maternal infections during gestation cause perturbed neuroimmune interactions and increased risk of neurodevelopmental disorders in the offspring. Using a maternal immune activation model with polyinosinic:polycytidylic acid (poly(I:C)), we investigated how maternal infections reshape the progeny hippocampal landscape. Poly(I:C) increased maternal type I interferon (IFN-I), disrupting neuronal transcriptional trajectories and excitatory synapse homeostasis in juvenile offspring. Poly(I:C) offspring microglia exhibited reduced expression of triggering receptor expressed on myeloid cells 2 (TREM2), a key regulator of synapse elimination and brain development, accompanied by impaired phagocytosis and suppressed IFN-I-responsive substate. Consistently, a blunted IFN-I signature was observed in postmortem tissues from schizophrenic patients. TREM2 deficiency was associated with aberrant maternal IFN-I and altered neuronal and microglial signatures in poly(I:C) offspring, highlighting its regulatory role in neurodevelopmental pathologies. Blocking maternal IFN-I signaling restored synaptic defects and TREM2 function, suggesting that monitoring IFN-I responses during pregnancy and targeting defective IFN-I cascades in the newborn may represent viable therapeutic approaches to mitigate neurodevelopmental dysfunctions.