Activated microglia cause metabolic disruptions in developmental cortical interneuron that persist in schizophrenia-patient-derived interneurons

The mechanisms by which prenatal immune activation increase risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs), known to be affected in schizophrenia (SCZ) when matured, from induced pluripotent stem cells (iPSCs) from healthy controls (HC) and SCZ patients, and cocultured them with or without activated microglia. Coculture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analysis, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by Alpha Lipoic Acid/Acetyl-L-Carnitine (ALA/ALC) treatments that boost mitochondrial function. Notably, activated microglia-conditioned medium altered metabolism in cINs and HC-derived iPSCs but not in SCZ-patient-derived iPSCs or in glutamatergic neurons. After removal of activated microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, suggesting an interaction between SCZ genetic backgrounds and environmental risk factors.