Astrocytic Ca2+ waves mediate activation of extrasynaptic NMDA receptors in hippocampal neurons to aggravate brain damage during ischemia
Astrocytic Ca2+ waves mediate activation of extrasynaptic NMDA receptors in hippocampal neurons to aggravate brain damage during ischemia
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DOI：
10.1016/j.nbd.2013.05.005
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发表时间：
2013-10-01
影响因子：
6.1
通讯作者：
Chai, Zhen
中科院分区：
文献类型：
--
作者：
Dong, Qi-ping;He, Jing-quan;Chai, Zhen
兴奋性毒性在缺血性卒中神经元损伤中起核心作用。虽然越来越多的证据表明，突触外NMDA受体的激活启动了神经元的死亡，但没有直接证据表明它们在缺血时被激活。在大鼠海马脑片上，我们检测到缺氧缺糖(OGD)诱导的CA1区锥体神经元慢内向电流(SICs)是由突触外NMDA受体介导的。此外，钙离子螯合剂BAPTA透析进入星形细胞网络可降低OGD诱发SICS的频率，提示突触外NMDA受体的激活依赖于星形胶质细胞的钙离子活性。为了进一步证明星形细胞钙活性的重要性，我们测试了三磷酸肌醇受体2型(IP3R2)基因敲除小鼠的海马片，该基因敲除了星形细胞钙活性。不出所料，OGD诱发SICS的频率降低。利用双光子钙离子成像，我们表征了星形胶质细胞的钙离子动力学。通过靶向光解控制单个星形胶质细胞内的钙离子水平，我们发现OGD促进了细胞间钙波的传播，而缝隙连接阻滞剂甘草酸(CBX)抑制了这一波的传播。CBX还可抑制OGD时星形胶质细胞网络的钙离子活性，降低SIC频率。在功能上，在IP3R2基因敲除小鼠和大鼠脑内注射CBX后，脑缺血造成的脑梗塞体积都减少了。我们的结果表明，星形胶质细胞网络中钙离子活性的增强在激活海马神经元突触外NMDA受体中起着关键作用，从而加强了脑缺血时的损伤。(C)2013 Elsevier Inc.保留所有权利。
Excitotoxicity plays a central role in the neuronal damage during ischemic stroke. Although growing evidence suggests that activation of extrasynaptic NMDA receptors initiates neuronal death, no direct evidence demonstrated their activation during ischemia. Using rat hippocampal slices, we detected oxygen-glucose deprivation (OGD) induced slow inward currents (SICs) mediated by extrasynaptic NMDA receptors in CA1 pyramidal neurons. Moreover, Ca2+ chelator BAPTA dialysis into astrocytic network decreased the frequency of OGD induced SICs, indicating that the activation of extrasynaptic NMDA receptors depended on astrocytic Ca2+ activity. To further demonstrate the importance of astrocytic Ca2+ activity, we tested hippocampal slices from inositol triphosphate receptor type 2 (IP3R2) knock-out mice which abolished the astrocytic Ca2+ activity. As expected, the frequency of OGD induced SICs was reduced. Using two-photon Ca2+ imaging, we characterized the astrocytic Ca2+ dynamics. By controlling Ca2+ level in the individual astrocytes using targeted photolysis, we found that OGD facilitated the propagation of intercellular Ca2+ waves, which were inhibited by gap junction blocker carbenoxolone (CBX). CBX also inhibited the Ca2+ activity of the astrocytic network and decreased the SIC frequency during OGD. Functionally, the infarct volumes from brain ischemia were reduced in IP3R2 knock-out mice and in rat intracerebrally delivered with CBX. Our results demonstrate that enhanced Ca2+ activity of the astrocytic network plays a key role on the activation of extrasynaptic NMDA receptors in hippocampal neurons, which enhances brain damage during ischemia. (C) 2013 Elsevier Inc. All rights reserved.