A mechanistic analysis of primary neurons from a maternal immune activation model of schizophrenia reveals complex I dysfunction and mitochondrial-driven neurodevelopmental deficits

Maternal immune activation (MIA) is a major environmental risk factor for schizophrenia, yet the early neuronal mechanisms linking embryonic immune challenges to neurodevelopmental disruption remain poorly defined. Here, we provide a detailed mechanistic characterization of primary cortical neurons derived from a Poly(I:C)-induced MIA model, revealing mitochondrial dysfunction as a central feature of the pathological phenotype. Cortical neurons cultured from the offspring of Poly(I:C)-treated females (embryonic day 14) exhibited a severely constrained bioenergetic state, characterized by increased basal respiration and ATP levels coupled with a significant reduction in both maximal respiration and spare respiratory capacity, indicating limited metabolic flexibility. This bioenergetic failure was accompanied by elevated mitochondrial superoxide production, consistent with a sustained redox imbalance. Concomitant alterations in mitochondrial proteins, including a marked reduction in NDUFS2 levels, further support the involvement of respiratory chain Complex I instability. Moreover, mitochondrial dynamics and content were profoundly disrupted, as evidenced by dysregulated OPA1, DRP1, and TOM20/TOM40 expression, which correlated with a reduced functional pool and a maladaptive remodeling toward enlarged, rounded, or fragmented mitochondria. Notably, these mitochondrial deficits directly paralleled a simplified dendritic arborization and impaired synaptic organization, thereby linking early bioenergetic and redox disturbances to structural neuronal impairments. Collectively, our findings identify mitochondrial dysfunction as a key mechanistic axis connecting prenatal inflammation to neurodevelopmental vulnerability, offering a cell-autonomous framework for how gestational immune challenges translate into structural deficits relevant to schizophrenia.