Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells.
Maternal inflammation contributes to brain overgrowth and autism-associated behaviors through altered redox signaling in stem and progenitor cells.
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DOI：
10.1016/j.stemcr.2014.09.004
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发表时间：
2014-11-11
影响因子：
5.9
通讯作者：
Kornblum, Harley I.
中科院分区：
文献类型：
--
作者：
Le Belle, Janel E.;Sperry, Jantzen;Ngo, Amy;Ghochani, Yasmin;Laks, Dan R.;Lopez-Aranda, Manuel;Silva, Alcino J.;Kornblum, Harley I.
一段原因不明的轻度脑过度生长已被确定为自闭症最常见的表型之一。在这里，我们测试了这样一个假设，即胚胎发育关键时期的母体炎症可以导致大脑过度生长和自闭症相关行为，这是神经干细胞功能改变的结果。在胚胎第9天用低剂量脂多糖处理的怀孕小鼠的后代大脑过度生长，在PTEN杂合子中的影响更明显。暴露在母体炎症中还会增强NADPH氧化酶(NOX)-PI3K通路信号，刺激神经干细胞和祖细胞的过度增殖，增加前脑小胶质细胞，并在受影响的幼鼠中产生异常的自闭症相关行为。我们的证据支持这样的观点，即神经干细胞氧化还原信号的产前神经炎性失调可以与潜在的遗传易感性协同作用，影响细胞对环境变化的细胞活性氧物种水平的反应。轻微的母体炎症会导致幼崽的大脑过度生长和自闭症行为母体炎症会增加干细胞分裂、ROS水平和PI3K激活遗传易感性在与MIR过度生长结合时会产生更大的脑过度生长，一些相关的异常行为可以通过抑制NOX来挽救在本文中，Kornblum和他的同事们展示了在胚胎发育的关键时期暴露于母体炎症和改变的细胞氧化还原平衡可以促进大脑过度生长和自闭症相关行为，这是神经干细胞功能改变的结果。此外，他们还证明了PTEN杂合性可以作为一种遗传易感性来产生更明显的大脑过度生长表型。
A period of mild brain overgrowth with an unknown etiology has been identified as one of the most common phenotypes in autism. Here, we test the hypothesis that maternal inflammation during critical periods of embryonic development can cause brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Pregnant mice treated with low-dose lipopolysaccharide at embryonic day 9 had offspring with brain overgrowth, with a more pronounced effect in PTEN heterozygotes. Exposure to maternal inflammation also enhanced NADPH oxidase (NOX)-PI3K pathway signaling, stimulated the hyperproliferation of neural stem and progenitor cells, increased forebrain microglia, and produced abnormal autism-associated behaviors in affected pups. Our evidence supports the idea that a prenatal neuroinflammatory dysregulation in neural stem cell redox signaling can act in concert with underlying genetic susceptibilities to affect cellular responses to environmentally altered cellular levels of reactive oxygen species. Mild maternal inflammation produces brain overgrowth and autistic behaviors in pups Maternal inflammation increases stem cell division, ROS levels, and PI3K activation Genetic susceptibility produces even greater brain overgrowth when combined with MIR Overgrowth and some associated abnormal behaviors can be rescued by inhibition of NOX In this article, Kornblum and colleagues show that exposure to maternal inflammation and an altered cellular redox balance during critical periods of embryonic development can promote brain overgrowth and autism-associated behaviors as a result of altered neural stem cell function. Additionally, they demonstrate that PTEN heterozygosity can act as a genetic susceptibility to produce a more pronounced brain overgrowth phenotype.
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DOI：
10.1056/nejmoa1307491
发表时间：
2014-03-27
期刊：
The New England journal of medicine
影响因子：
--
作者：
Stoner R;Chow ML;Boyle MP;Sunkin SM;Mouton PR;Roy S;Wynshaw-Boris A;Colamarino SA;Lein ES;Courchesne E
通讯作者：
Courchesne E
影响因子：
4.7
作者：
Klein, Steven;Sharifi-Hannauer, Pantea;Martinez-Agosto, Julian A.
通讯作者：
Martinez-Agosto, Julian A.
影响因子：
4
作者：
Bill, Brent R.;Geschwind, Daniel H.
通讯作者：
Geschwind, Daniel H.
影响因子：
10.6
作者：
Sacco, Roberto;Militerni, Roberto;Persico, Antonio M.
通讯作者：
Persico, Antonio M.
DOI：
10.1073/pnas.0509939103
发表时间：
2006-01-03
影响因子：
11.1
作者：
Groszer, M;Erickson, R;Wu, H
通讯作者：
Wu, H