Herrero Felisa, Mueller Flavia S, Gruchot Joel, Küry Patrick, Weber-Stadlbauer Ulrike, Meyer Urs
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
Department of Neurology, Medical Faculty, Heinrich-Heine-University Düsseldorf, Düsseldorf, Germany.
Brain Behav Immun. 2023 Jan;107:201-214. doi: 10.1016/j.bbi.2022.10.006. Epub 2022 Oct 12.
Endogenous retroviruses (ERVs) are ancestorial retroviral elements that were integrated into the mammalian genome through germline infections and insertions during evolution. While increased ERV expression has been repeatedly implicated in psychiatric and neurodevelopmental disorders, recent evidence suggests that aberrant endogenous retroviral activity may contribute to biologically defined subgroups of psychotic disorders with persisting immunological dysfunctions. Here, we explored whether ERV expression is altered in a mouse model of maternal immune activation (MIA), a transdiagnostic environmental risk factor of psychiatric and neurodevelopmental disorders. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Murine ERV transcripts were quantified in the placentae and fetal brains shortly after poly(I:C)-induced MIA, as well as in adult offspring that were stratified according to their behavioral profiles. We found that MIA increased and reduced levels of class II ERVs and syncytins, respectively, in placentae and fetal brain tissue. We also revealed abnormal ERV expression in MIA-exposed offspring depending on whether they displayed overt behavioral anomalies or not. Taken together, our findings provide a proof of concept that an inflammatory stimulus, even when initiated in prenatal life, has the potential of altering ERV expression across fetal to adult stages of development. Moreover, our data highlight that susceptibility and resilience to MIA are associated with differential ERV expression, suggesting that early-life exposure to inflammatory factors may play a role in determining disease susceptibility by inducing persistent alterations in the expression of endogenous retroviral elements.
内源性逆转录病毒（ERVs）是祖先逆转录病毒元件，在进化过程中通过种系感染和插入整合到哺乳动物基因组中。虽然ERV表达增加一再与精神疾病和神经发育障碍有关，但最近的证据表明，异常的内源性逆转录病毒活性可能导致具有持续免疫功能障碍的精神病性障碍的生物学定义亚组。在这里，我们探讨了在母体免疫激活（MIA）的小鼠模型中ERV表达是否发生改变，MIA是精神疾病和神经发育障碍的一种跨诊断环境风险因素。在妊娠第12天给C57BL/6N小鼠的母体注射聚肌胞苷酸（poly(I:C)）来诱导MIA。在poly(I:C)诱导的MIA后不久，以及在根据其行为特征分层的成年后代中，对胎盘和胎儿大脑中的小鼠ERV转录本进行定量。我们发现，MIA分别增加和降低了胎盘和胎儿脑组织中II类ERV和合胞素的水平。我们还发现，暴露于MIA的后代中ERV表达异常，这取决于它们是否表现出明显的行为异常。综上所述，我们的研究结果提供了一个概念验证，即即使在产前生活中引发的炎症刺激，也有可能在从胎儿到成年的发育阶段改变ERV表达。此外，我们的数据强调，对MIA的易感性和恢复力与ERV表达的差异有关，这表明生命早期暴露于炎症因子可能通过诱导内源性逆转录病毒元件表达的持续改变，在决定疾病易感性方面发挥作用。
