Inhibition of Reactive Astrocytes with Fluorocitrate Ameliorates Learning and Memory Impairment Through Upregulating CRTC1 and Synaptophysin in Ischemic Stroke Rats
Inhibition of Reactive Astrocytes with Fluorocitrate Ameliorates Learning and Memory Impairment Through Upregulating CRTC1 and Synaptophysin in Ischemic Stroke Rats
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用氟柠檬酸抑制反应性星形胶质细胞通过上调 CRTC1 和突触素改善缺血性中风大鼠的学习和记忆障碍
DOI：
10.1007/s10571-019-00709-0
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发表时间：
2019-11-01
影响因子：
4
通讯作者：
Jin, Xinchun
中科院分区：
文献类型：
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作者：
Zhang, Xinyu;Shen, Xianzhi;Jin, Xinchun
缺血性中风常引起运动和认知障碍。在动物脑卒中模型中，已在缺血海马中观察到神经胶质纤维酸性蛋白（GFAP）和连接蛋白43 （Cx43）蛋白水平升高所反映的神经胶质间隙连接通讯失调，并与认知障碍有关。在这里，我们验证了反应性星形胶质细胞介导的突触素（SYP）和creb调节的转录共激活因子1 （CRTC1）的缺失导致缺血性卒中后胶质间隙连接通信功能障碍和记忆障碍的假设。雄性Sprague-Dawley大鼠大脑中动脉闭塞90 min，再灌注7 d。将星形胶质细胞三羧酸循环的可逆抑制剂氟柠檬酸（1 nmol）从再灌注前立即开始，每2天1次注射于MCAO大鼠右侧脑室。Morris水迷宫评估记忆，结合western blotting和免疫染色检测海马蛋白的表达和分布。我们的研究结果表明，缺血性中风引起明显的记忆障碍，并伴有海马组织中GFAP和Cx43蛋白水平的升高。此外，海马组织中SYP、CRTC1、髓鞘碱性蛋白、高迁移率group-box-1等记忆相关关键蛋白水平显著降低。值得注意的是，氟柠檬酸盐抑制反应性星形胶质细胞可显著逆转缺血性中风引起的上述变化。综上所述，我们的研究结果表明，在再灌注前立即用氟柠檬酸抑制反应性星形胶质细胞可能通过上调CRTC1和SYP来保护缺血性卒中诱导的记忆损伤。
Ischemic stroke often causes motor and cognitive deficits. Deregulated glia gap junction communication, which is reflected by increased protein levels of glial fibrillary acidic protein (GFAP) and connexin 43 (Cx43), has been observed in ischemic hippocampus and has been associated with cognitive impairment in animal stroke models. Here, we tested the hypothesis that reactive astrocytes-mediated loss of synaptophysin (SYP) and CREB-regulated transcription coactivator 1 (CRTC1) contribute to dysfunction in glia gap junction communication and memory impairment after ischemic stroke. Male Sprague–Dawley rats were subjected to a 90-min middle cerebral artery occlusion (MCAO) with 7-day reperfusion. Fluorocitrate (1 nmol), the reversible inhibitor of the astrocytic tricarboxylic acid cycle, was injected into the right lateral ventricle of MCAO rats once every 2 days starting immediately before reperfusion. The Morris water maze was used to assess memory in conjunction with western blotting and immunostaining to detect protein expression and distribution in the hippocampus. Our results showed that ischemic stroke caused significant memory impairment accompanied by increased protein levels of GFAP and Cx43 in hippocampal tissue. In addition, the levels of several key memory-related important proteins including SYP, CRTC1, myelin basic protein and high-mobility group-box-1 were significantly reduced in the hippocampal tissue. Of note, inhibition of reactive astrocytes with fluorocitrate was shown to significantly reverse the above noted changes induced by ischemic stroke. Taken together, our findings demonstrate that inhibiting reactive astrocytes with fluorocitrate immediately before reperfusion may protect against ischemic stroke-induced memory impairment through the upregulation of CRTC1 and SYP.