McDonald Chloë R, Cahill Lindsay S, Ho Keith T, Yang Jimmy, Kim Hani, Silver Karlee L, Ward Peter A, Mount Howard T, Liles W Conrad, Sled John G, Kain Kevin C
Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; SAR Laboratories, Sandra Rotman Centre for Global Health, University Health Network-Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada.
Mouse Imaging Centre, Hospital for Sick Children, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
PLoS Pathog. 2015 Sep 24;11(9):e1005140. doi: 10.1371/journal.ppat.1005140. eCollection 2015 Sep.
The in utero environment profoundly impacts childhood neurodevelopment and behaviour. A substantial proportion of pregnancies in Africa are at risk of malaria in pregnancy (MIP) however the impact of in utero exposure to MIP on fetal neurodevelopment is unknown. Complement activation, in particular C5a, may contribute to neuropathology and adverse outcomes during MIP. We used an experimental model of MIP and standardized neurocognitive testing, MRI, micro-CT and HPLC analysis of neurotransmitter levels, to test the hypothesis that in utero exposure to malaria alters neurodevelopment through a C5a-C5aR dependent pathway. We show that malaria-exposed offspring have persistent neurocognitive deficits in memory and affective-like behaviour compared to unexposed controls. These deficits were associated with reduced regional brain levels of major biogenic amines and BDNF that were rescued by disruption of C5a-C5aR signaling using genetic and functional approaches. Our results demonstrate that experimental MIP induces neurocognitive deficits in offspring and suggest novel targets for intervention.
子宫内环境对儿童神经发育和行为有深远影响。非洲相当大比例的孕妇面临妊娠疟疾（MIP）风险，然而子宫内暴露于MIP对胎儿神经发育的影响尚不清楚。补体激活，特别是C5a，可能在MIP期间导致神经病理学和不良后果。我们使用MIP实验模型以及标准化神经认知测试、MRI、微型CT和神经递质水平的HPLC分析，来检验子宫内暴露于疟疾通过C5a - C5aR依赖途径改变神经发育这一假设。我们发现，与未暴露的对照组相比，暴露于疟疾的后代在记忆和情感样行为方面存在持续的神经认知缺陷。这些缺陷与大脑主要生物胺和脑源性神经营养因子（BDNF）的区域水平降低有关，而通过基因和功能方法破坏C5a - C5aR信号传导可挽救这些缺陷。我们的结果表明，实验性MIP会导致后代出现神经认知缺陷，并提示了新的干预靶点。
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