School of Life Science and Technology, Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu, Sichuan 610054, China.
Department of Histology and Embryology, School of Basic Medical Sciences, Southwest Medical University, Luzhou, Sichuan 646000, China.
Neurobiol Dis. 2019 May;125:1-13. doi: 10.1016/j.nbd.2019.01.005. Epub 2019 Jan 17.
Maternal infection during pregnancy is an important factor involved in the pathogenesis of brain disorders in the offspring. Mounting evidence from maternal immune activation (MIA) animals indicates that microglial priming may contribute to neurodevelopmental abnormalities in the offspring. Because peroxisome proliferator-activated receptor gamma (PPARγ) activation exerts neuroprotective effects by regulating neuroinflammatory response, it is a pharmacological target for treating neurogenic disorders. We investigated the effect of PPARγ-dependent microglial activation on neurogenesis and consequent behavioral outcomes in male MIA-offspring. Pregnant dams on gestation day 18 received Poly(I:C) (1, 5, or 10 mg/kg; i.p.) or the vehicle. The MIA model that received 10 mg/kg Poly(I:C) showed significantly increased inflammatory responses in the maternal serum and fetal hippocampus, followed by cognitive deficits, which were highly correlated with hippocampal neurogenesis impairment in prepubertal male offspring. The microglial population in hippocampus increased, displayed decreased processes and larger soma, and had a higher expression of the CD11b, which is indicative of the M1 phenotype (classical activation). Activation of the PPARγ pathway by pioglitazone in the MIA offspring rescued the imbalance of the microglial activation and ameliorated the MIA-induced suppressed neurogenesis and cognitive impairments and anxiety behaviors. In an in vitro experiment, PPARγ-induced M2 microglia (alternative activation) promoted the proliferation and differentiation of neural precursor cells. These results indicated that the MIA-induced long-term changes in microglia phenotypes were associated with hippocampal neurogenesis and neurobehavioral abnormalities in offspring. Modulation of the microglial phenotypes was associated with a PPARγ-mediated neuroprotective mechanism in the MIA offspring and may serve as a potential therapeutic approach for prenatal immune activation-induced neuropsychiatric disorders.
母体感染是导致后代大脑疾病发病机制的一个重要因素。越来越多的母体免疫激活（MIA）动物的证据表明，小胶质细胞的激活可能导致后代神经发育异常。过氧化物酶体增殖物激活受体γ（PPARγ）通过调节神经炎症反应发挥神经保护作用，因此它是治疗神经源性疾病的药物靶点。我们研究了 PPARγ 依赖性小胶质细胞激活对雄性 MIA 后代神经发生和随后的行为结果的影响。妊娠第 18 天的孕鼠接受 Poly(I:C)（1、5 或 10mg/kg；腹腔注射）或载体。接受 10mg/kg Poly(I:C)的 MIA 模型显示母体血清和胎儿海马中的炎症反应明显增加，随后出现认知缺陷，这与青春期前雄性后代海马神经发生受损高度相关。海马中小胶质细胞数量增加，突起减少，胞体增大，CD11b 表达增加，表明 M1 表型（经典激活）。在 MIA 后代中，吡格列酮激活 PPARγ 通路可挽救小胶质细胞激活的失衡，改善 MIA 诱导的神经发生抑制、认知障碍和焦虑行为。在体外实验中，PPARγ 诱导的 M2 小胶质细胞（替代激活）促进神经前体细胞的增殖和分化。这些结果表明，MIA 诱导的小胶质细胞表型的长期变化与后代海马神经发生和神经行为异常有关。小胶质细胞表型的调节与 MIA 后代中 PPARγ 介导的神经保护机制有关，可能成为产前免疫激活诱导的神经精神疾病的潜在治疗方法。
