Sevoflurane impairs learning and memory of the developing brain through post-transcriptional inhibition of CCNA2 via microRNA-19-3p
Sevoflurane impairs learning and memory of the developing brain through post-transcriptional inhibition of CCNA2 via microRNA-19-3p
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DOI：
10.18632/aging.101673
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发表时间：
2018-12
期刊：
影响因子：
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通讯作者：
Xin Zhao;Yanwu Jin;Haibo Li;Yuxiu Jia;Yuelan Wang
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文献类型：
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作者：
Xin Zhao;Yanwu Jin;Haibo Li;Yuxiu Jia;Yuelan Wang
七氟烷（SEVO）诱导的学习和记忆障碍的分子机制尚不清楚。具体而言，先前尚未报道microRNA（miRNAs）在暴露于SEVO的发育中的脑中控制神经元增殖的作用。本实验研究了SEVO对新生大鼠神经细胞增殖及学习记忆的影响。我们发现SEVO暴露显著降低神经元细胞增殖，降低脑内BDNF水平，并在Morris水迷宫实验和正迷宫辨别回避任务（PM-DAT）中损害新生大鼠的学习和记忆，可能通过下调CCNA 2蛋白。接下来，我们使用生物信息学工具来预测CCNA 2结合microRNAs（miRNAs），发现miR-19- 3 p在暴露于SEVO的神经元中上调。此外，miR-19- 3 p在人类神经细胞系HCN-2中功能性地抑制CCNA 2的蛋白质翻译。此外，颅内注射携带CMV启动子下的miR-19- 3 p反义核酸的腺相关病毒到新生大鼠中显著减轻SEVO手术诱导的神经元细胞增殖以及大鼠的学习和记忆障碍。总之，我们的数据表明，SEVO诱导的miR-19- 3 p转录后上调抑制CCNA 2，这有助于新生大鼠的SEVO相关的学习和记忆障碍。
The molecular mechanisms underlying sevoflurane (SEVO)-induced impairment of learning and memory remain unclear. Specifically, a role of microRNAs (miRNAs) in the control of the neuron proliferation in the developing brain exposed to SEVO has not been reported previously. Here, we studied the effects of SEVO exposure on the neural cell proliferation, and on the learning and memory of neonatal rats. We found that SEVO exposure significantly decreased neuron cell proliferation, reduced BDNF levels in brain, and impaired learning and memory of neonatal rats in Morris water maze test and Plus-Maze discriminative avoidance task (PM-DAT), likely through downregulation of CCNA2 protein. Next, we used bioinformatic tools to predict CCNA2-binding microRNAs (miRNAs), and found that miR-19-3p was upregulated in neurons exposed to SEVO. Moreover, miR-19-3p functionally inhibited the protein translation of CCNA2 in a human neural cell line, HCN-2. Furthermore, intracranial injection of adeno-associated virus carrying antisense of miR-19-3p under a CMV promoter into the neonatal rats significantly alleviated SEVO exposure-induced impairment of neuron cell proliferation, as well as the learning and memory of the rats. Together, our data suggest that SEVO-induced upregulation of miR-19-3p post-transcriptionally inhibits CCNA2, which contributes to the SEVO-associated impairment of learning and memory of the neonatal rats.