Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia
Astroglial dysfunctions drive aberrant synaptogenesis and social behavioral deficits in mice with neonatal exposure to lengthy general anesthesia
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星形胶质细胞功能障碍导致新生儿长期全身麻醉小鼠异常突触发生和社会行为缺陷
DOI：
10.1371/journal.pbio.3000086
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发表时间：
2019
期刊：
影响因子：
9.8
通讯作者：
Jiang Ruotian
中科院分区：
文献类型：
--
作者：
Zhou Bin;Chen Lingmin;Liao Ping;Huang Lu;Chen Zhuo;Liao Daqing;Yang Linghui;Wang Jing;Yu Guoqiang;Wang Li;Zhang Jianguo;Zuo Yunxia;Liu Jin;Jiang Ruotian
长期使用全身麻醉药(GAS)会导致发育中大脑的神经行为障碍，这引起了严重的临床关注，以至于美国食品和药物管理局(FDA)对3岁以下儿童使用GAS发出了警告。然而，气体诱导的神经毒性的分子和细胞机制在很大程度上仍不清楚。在此，我们报道了七氟醚(Sevo)，一种儿科常用的GA，在时空上与突触过度生长相关的星形胶质细胞形态发生受损，突触功能在发育皮质中以区域、暴露长度和年龄特有的方式降低。Sevo急性和慢性地破坏了星形胶质细胞的钙稳态，导致了Ezrin的下调，Ezrin是一种肌动蛋白结合膜结合蛋白，我们发现Ezrin在星形胶质细胞体内的形态发生中起关键作用。重要的是，星形胶质细胞Ezrin的过表达挽救了长期暴露于Sevo的发育中小鼠的星形胶质细胞和神经元功能障碍，并完全纠正了社会行为缺陷。我们的数据揭示，除了神经元，星形胶质细胞可能是GAS发挥毒性作用的重要靶点，星形胶质细胞的形态完整性对突触发生和神经行为至关重要。
Lengthy use of general anesthetics (GAs) causes neurobehavioral deficits in the developing brain, which has raised significant clinical concerns such that the United States Food and Drug Administration (FDA) is warning on the use of GAs in children younger than 3 years. However, the molecular and cellular mechanisms for GAs-induced neurotoxicity remain largely unknown. Here, we report that sevoflurane (Sevo), a commonly used GA in pediatrics, caused compromised astrocyte morphogenesis spatiotemporally correlated to synaptic overgrowth, with reduced synaptic function in developing cortex in a regional-, exposure-length-, and age-specific manner. Sevo disrupted astrocyte Ca2+ homeostasis both acutely and chronically, which led to the down-regulation of Ezrin, an actin-binding membrane-bound protein, which we found was critically involved in astrocyte morphogenesis in vivo. Importantly, overexpression of astrocyte Ezrin rescued astrocytic and neuronal dysfunctions and fully corrected deficits in social behaviors in developing mice with lengthy Sevo exposure. Our data uncover that, in addition to neurons, astrocytes may represent important targets for GAs to exert toxic effects and that astrocyte morphological integrity is crucial for synaptogenesis and neurological behaviors.