The mechanisms by which prenatal immune activation increase the risk for neuropsychiatric disorders are unclear. Here, we generated developmental cortical interneurons (cINs)—which are known to be affected in schizophrenia (SCZ) when matured—from induced pluripotent stem cells (iPSCs) derived from healthy controls (HCs) and individuals with SCZ and co-cultured them with or without activated microglia. Co-culture with activated microglia disturbed metabolic pathways, as indicated by unbiased transcriptome analyses, and impaired mitochondrial function, arborization, synapse formation and synaptic GABA release. Deficits in mitochondrial function and arborization were reversed by alpha lipoic acid and acetyl-l-carnitine treatments, which boost mitochondrial function. Notably, activated-microglia-conditioned medium altered metabolism in cINs and iPSCs from HCs but not in iPSCs from individuals with SCZ or in glutamatergic neurons. After removal of activated-microglia-conditioned medium, SCZ cINs but not HC cINs showed prolonged metabolic deficits, which suggests that there is an interaction between SCZ genetic backgrounds and environmental risk factors.

产前免疫激活增加神经精神疾病风险的机制尚不清楚。在这里，我们从来自健康对照 (HC) 和 SCZ 个体的诱导多能干细胞 (iPSC) 中生成了发育皮质中间神经元 (cIN)——已知它们在成熟时会在精神分裂症 (SCZ) 中受到影响，并将它们与或没有激活的小胶质细胞。无偏转录组分析表明，与活化的小胶质细胞共培养扰乱了代谢途径，并损害了线粒体功能、树枝状化、突触形成和突触 GABA 释放。α硫辛酸和乙酰-l可以逆转线粒体功能和树枝状形成的缺陷- 肉碱治疗，可促进线粒体功能。值得注意的是，活化的小胶质细胞条件培养基改变了来自 HCs 的 cIN 和 iPSCs 的代谢，但不会改变来自 SCZ 个体或谷氨酸能神经元的 iPSCs。去除活化的小胶质细胞条件培养基后，SCZ cINs 而不是 HC cINs 表现出长期的代谢缺陷，这表明 SCZ 遗传背景和环境风险因素之间存在相互作用。