Neuroinflammation leads to region-dependent alterations in astrocyte gap junction communication and hemichannel activity.
Neuroinflammation leads to region-dependent alterations in astrocyte gap junction communication and hemichannel activity.
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DOI：
10.1523/jneurosci.5247-10.2011
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发表时间：
2011-01-12
期刊：
影响因子：
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通讯作者：
Kielian T
中科院分区：
文献类型：
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作者：
Karpuk N;Burkovetskaya M;Fritz T;Angle A;Kielian T
炎症会减弱培养的星形胶质细胞中的间隙连接（GJ）通讯。在这里，我们利用一个良好表征的实验性脑脓肿模型作为工具来探究中枢神经系统炎症环境对星形胶质细胞 GJ 通讯和电生理特性的影响。在纹状体中金黄色葡萄球菌感染后 3 或 7 天，对 GFAP-GFP 小鼠急性脑切片中的 GFP 阳性星形胶质细胞进行全细胞膜片钳记录。星形胶质细胞 GJ 通讯在紧邻脓肿边缘的区域显着减弱，并随着距脓肿本身距离的增加逐渐增加至未感染大脑的典型水平。相反，脓肿边缘的星形胶质细胞表现出半通道活性，通过增强的 EtBr 摄取来明显看出，这种活性可以被几种药理学抑制剂阻断，包括连接蛋白 43 (Cx43) 模拟肽 Gap26、carbenoxolone、pannexin1 (Panx1) 模拟肽 10Panx1 和丙磺舒。然而，半通道开放是短暂的，感染后第 3 天而非第 7 天在脓肿附近观察到星形细胞摄取 EtBr。第 3 天的半通道活性区域依赖性模式与脓肿边缘 Cx43、Cx30、Panx1 和谷氨酸转运蛋白（GLT 和 GLAST）表达的增加直接相关。星形胶质细胞静息膜电位和输入电导的变化与观察到的 GJ 通讯和半通道活动的变化相关。总的来说，这些发现表明星形胶质细胞耦合和电特性在原发炎症部位附近受到的影响最为显着，并揭示了急性感染期间 GJ 通道与半通道的开放状态之间的相反关系。这种关系可能延伸到以炎症为代表的其他中枢神经系统疾病。
Inflammation attenuates gap junction (GJ) communication in cultured astrocytes. Here we utilized a well-characterized model of experimental brain abscess as a tool to query effects of the CNS inflammatory milieu on astrocyte GJ communication and electrophysiological properties. Whole-cell patch-clamp recordings were performed on GFP-positive astrocytes in acute brain slices from GFAP-GFP mice at 3 or 7 days following S. aureus infection in the striatum. Astrocyte GJ communication was significantly attenuated in regions immediately surrounding the abscess margins and progressively increased to levels typical of uninfected brain with increasing distance from the abscess proper. Conversely, astrocytes bordering the abscess demonstrated hemichannel activity as evident by enhanced EtBr uptake that could be blocked by several pharmacological inhibitors including the connexin 43 (Cx43) mimetic peptide Gap26, carbenoxolone, the pannexin1 (Panx1) mimetic peptide 10Panx1, and probenecid. However, hemichannel opening was transient with astrocytic EtBr uptake observed near the abscess at day 3 but not day 7 post-infection. The region-dependent pattern of hemichannel activity at day 3 directly correlated with increases in Cx43, Cx30, Panx1, and glutamate transporter expression (GLT and GLAST) along the abscess margins. Changes in astrocyte resting membrane potential and input conductance correlated with the observed changes in GJ communication and hemichannel activity. Collectively, these findings indicate that astrocyte coupling and electrical properties are most dramatically affected near the primary inflammatory site and reveal an opposing relationship between the open states of GJ channels versus hemichannels during acute infection. This relationship may extend to other CNS diseases typified with an inflammatory component.