Maternal immune activation causes sex-specific impairment of microglial function during prefrontal cortex development.

Gestational maternal immune activation (MIA) has been recognized as a risk factor for neurodevelopmental disorders (NDDs) later in life. Furthermore, sex is a significant modifying factor for NDDs. Microglia, the resident immune cells of the brain, appear to be critical mediators of MIA-associated NDD pathology and are known to play a pivotal role in the pathological process of MIA-induced behavioral abnormalities. However, the exact mechanisms linking microglial perturbations to neurodevelopmental abnormalities in adult MIA offspring remain unclear. Here, we demonstrated that MIA induced sex-specific behavioral deficits in male offspring. Bulk RNA sequencing revealed pronounced transcriptional dysregulation related to synaptic transmission and immune responses specifically in males. Single-cell RNA sequencing further indicated that MIA blunted microglial reactivity in the developing prefrontal cortex (PFC) of male offspring. Consistently, further validation confirmed that MIA led to sex-specific synaptic pruning deficits, accompanied by a reduction in the number of proliferating microglia specifically in males during PFC development. As a consequence, male MIA offspring exhibited increased synaptic protein levels in the PFC. Our findings show that impaired microglial activity may contribute to sex-biased neurodevelopmental abnormalities induced by MIA, providing new insights into the neuroimmune mechanisms underlying NDDs.