Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway.
Early Isoflurane Exposure Impairs Synaptic Development in Fmr1 KO Mice via the mTOR Pathway.
复制标题
早期接触异氟烷会通过 mTOR 通路损害 Fmr1 KO 小鼠的突触发育。
DOI：
10.1007/s11064-021-03301-5
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发表时间：
2021
影响因子：
4.4
通讯作者：
Mintz,CDavid
中科院分区：
文献类型：
--
作者：
Wen,Jieqiong;Xu,Jing;Mathena,RPaige;Choi,JunH;Mintz,CDavid
全身麻醉药（GA）可能会导致大脑发育中断，GA暴露在既存神经发育疾病的背景下的影响尚不清楚。我们测试了这一假设，即突触发育在脆性X综合征小鼠模型中比在WT小鼠中更容易受到GA诱导的缺陷的影响，并询问它们是否与mTOR通路有关，mTOR通路是一种与麻醉毒性和脆性X综合征有关的信号系统。将出生后早期的WT和Fmr 1-KO小鼠暴露于异氟烷，并在成年后收集脑切片。从WT和Fmr 1-KO小鼠分离的原代神经元培养物在发育期间暴露于异氟烷，在某些情况下用雷帕霉素处理，并在成熟时进行免疫组织化学处理。对突触标志物和mTOR通路活性标志物进行定量免疫荧光显微镜检查。异氟烷暴露导致Synpasin-1、PSD-95和点状桥蛋白减少，在Fmr 1-KO小鼠中显著低于WT小鼠。在细胞培养中也发现了类似的结果，其中雷帕霉素治疗改善了突触丢失。与WT小鼠相比，早期发育暴露于异氟烷导致Fmr 1- KO小鼠更严重的突触丢失，这种效应是由mTOR通路活性的病理性增加介导的。
General anesthetics (GAs) may cause disruptions in brain development, and the effect of GA exposure in the setting of pre-existing neurodevelopmental disease is unknown. We tested the hypothesis that synaptic development is more vulnerable to GA-induced deficits in a mouse model of fragile X syndrome than in WT mice and asked whether they were related to the mTOR pathway, a signaling system implicated in both anesthesia toxicity and fragile X syndrome. Early postnatal WT andFmr1-KO mice were exposed to isoflurane and brain slices were collected in adulthood. Primary neuron cultures isolated from WT andFmr1-KO mice were exposed to isoflurane during development, in some cases treated with rapamycin, and processed for immunohistochemistry at maturity. Quantitative immunofluorescence microscopy was conducted for synaptic markers and markers of mTOR pathway activity. Isoflurane exposure caused reduction in Synpasin-1, PSD-95, and Gephyrin puncta that was significantly lower inFmr1-KO mice than in WT mice. Similar results were found in cell culture, where synapse loss was ameliorated with rapamycin treatment. Early developmental exposure to isoflurane causes more profound synapse loss inFmr1- KO than WT mice, and this effect is mediated by a pathologic increase in mTOR pathway activity.