Weber-Stadlbauer Ulrike, Richetto Juliet, Zwamborn Ramona A J, Slieker Roderick C, Meyer Urs
Institute of Pharmacology and Toxicology, University of Zurich-Vetsuisse, Zurich, Switzerland.
Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland.
Neuropsychopharmacology. 2021 Jan;46(2):404-412. doi: 10.1038/s41386-020-00855-w. Epub 2020 Sep 12.
Prenatal exposure to infectious and/or inflammatory insults is increasingly recognized to contribute to the etiology of psychiatric disorders with neurodevelopmental components. Recent research using animal models suggests that maternal immune activation (MIA) can induce transgenerational effects on brain and behavior, possibly through epigenetic mechanisms. Using a mouse model of MIA that is based on gestational treatment with the viral mimeticpoly(I:C) (= polyriboinosinic-polyribocytidilic acid), the present study explored whether the transgenerational effects of MIA are extendable to dopaminergic dysfunctions. We show that the direct descendants born to poly(I:C)-treated mothers display signs of hyperdopaminergia, as manifested by a potentiated sensitivity to the locomotor-stimulating effects of amphetamine (Amph) and increased expression of tyrosine hydroxylase (Th) in the adult ventral midbrain. In stark contrast, second- and third-generation offspring of MIA-exposed ancestors displayed blunted locomotor responses to Amph and reduced expression of Th. Furthermore, we found increased DNA methylation at the promoter region of the dopamine-specifying factor, nuclear receptor-related 1 protein (Nurr1), in the sperm of first-generation MIA offspring and in the ventral midbrain of second-generation offspring of MIA-exposed ancestors. The latter effect was further accompanied by reduced mRNA levels of Nurr1 in this brain region. Together, our results suggest that MIA has the potential to modify dopaminergic functions across multiple generations with opposite effects in the direct descendants and their progeny. The presence of altered DNA methylation in the sperm of MIA-exposed offspring highlights the possibility that epigenetic processes in the male germline play a role in the transgenerational effects of MIA.
产前暴露于感染和/或炎症刺激越来越被认为是导致具有神经发育成分的精神障碍病因的一个因素。最近使用动物模型的研究表明，母体免疫激活（MIA）可能通过表观遗传机制对大脑和行为产生跨代影响。本研究使用基于用病毒模拟物聚肌苷酸-聚胞苷酸（poly(I:C)）进行孕期治疗的MIA小鼠模型，探讨了MIA的跨代影响是否可扩展至多巴胺能功能障碍。我们发现，经聚肌苷酸-聚胞苷酸处理的母亲所生的直接后代表现出多巴胺能亢进的迹象，表现为对苯丙胺（Amph）的运动刺激作用敏感性增强，以及成年腹侧中脑酪氨酸羟化酶（Th）表达增加。与之形成鲜明对比的是，暴露于MIA的祖先的第二代和第三代后代对Amph的运动反应减弱，Th表达降低。此外，我们发现第一代MIA后代的精子以及暴露于MIA的祖先的第二代后代的腹侧中脑中，多巴胺特异性因子核受体相关1蛋白（Nurr1）启动子区域的DNA甲基化增加。后一种效应还伴随着该脑区Nurr1 mRNA水平的降低。总之，我们的结果表明，MIA有可能在多代中改变多巴胺能功能，对直接后代及其子代产生相反的影响。暴露于MIA的后代精子中DNA甲基化的改变表明，雄性生殖系中的表观遗传过程可能在MIA的跨代影响中发挥作用。
