Maternal immune activation induces sex-dependent metabolic, epigenetic and GABAergic trajectories in the hippocampus.
Maternal immune activation (MIA) is associated with increased risk of neurodevelopmental disorders, including schizophrenia. Research demonstrates sex-specific responses to MIA, yet how MIA interacts with intrinsic sex differences during brain development remains unclear. Here, we investigated how poly(I:C)-induced MIA alters metabolic, epigenetic and inhibitory developmental trajectories. Female, but not male, poly(I:C) offspring exhibited an object location memory deficit, implicating the hippocampus as a vulnerable region. Using RNA sequencing of the prenatal hippocampus, we identified a pronounced female-specific transcriptional response to MIA, with enrichment of mitochondrial and chromatin-related pathways. Concurrently, intrinsic sex differences indicated divergent metabolic/mitochondrial maturation, such as increased expression of Ppargc1a (encoding peroxisome proliferator-activated receptor gamma coactivator 1-α) and increased antioxidant activity in females compared to males, consistent with greater metabolic capacity. MIA interacted with these trajectories, producing sex-dependent effects on mitochondrial dynamics which coincided with signatures of a more permissive chromatin state, including reduced histone deacetylase activity, increased histone acetylation and reduced H3K27 methylation. In adulthood, MIA offspring showed altered chloride transporter expression, with a shift toward NKCC1 (a molecular driver of the GABAergic switch) and evidence of promoter-level epigenetic regulation, most evident in females. This coincided with reduced clusters of the scaffolding protein gephyrin in adolescent poly(I:C) females, consistent with altered inhibitory synapse maturation. Together, these findings indicate that sex-specific metabolic programming shapes the neurodevelopmental response to MIA and contributes to the observed sex differences in brain and behavioural response. Understanding typical sex differences in mitochondrial development is critical for predicting vulnerability and informing therapeutic treatment.