Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury
Specific gap junctions enhance the neuronal vulnerability to brain traumatic injury
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DOI：
10.1523/jneurosci.22-03-00644.2002
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发表时间：
2002-02-01
影响因子：
5.3
通讯作者：
Velazquez, JLP
中科院分区：
文献类型：
--
作者：
Frantseva, MV;Kokarovtseva, L;Velazquez, JLP
创伤性脑损伤导致神经元损失和相关的神经功能缺损。虽然大多数关于创伤性损伤的研究都集中在突触或离子机制上，但通过间隙连接进行的细胞间直接通讯的可能作用尚未被探索。缝隙连接直接连接偶联细胞的胞浆，因此，它们提供了一种在细胞间传播应激信号的途径。我们使用体外创伤模型研究了间隙连接通讯（GJC）对细胞死亡的贡献。在器官型海马切片的远端CA1区上由重量下降引起的冲击损伤导致谷氨酸依赖性细胞损失。差距连接阻断剂甘珀酸和辛醇显著降低创伤后细胞死亡，通过碘化丙啶染色在撞击后72小时内测量。染料偶联在锥体层的损伤后立即增强，并在随后的24 hr.To确定是否参与特定的连接蛋白的创伤诱导的细胞死亡的传播，我们使用的器官型切片连接蛋白43（Cx43）基因敲除小鼠，以及急性敲除孵育反义寡核苷酸。同时敲低两个神经元连接蛋白导致显着的神经保护。来自空突变Cx43小鼠的切片，以及急性Cx43敲低，也显示出撞击后细胞死亡减少。差距连接阻断剂减轻了创伤引起的突触功能损害，如通过电生理场电位记录测量的。这些结果表明，GJC增强了细胞对创伤性损伤的脆弱性。因此，特异性缝隙连接可能是一种新的靶点，以减少对大脑的损伤和继发性损伤，并最大限度地从创伤中恢复。
Traumatic brain injury results in neuronal loss and associated neurological deficits. Although most research on the factors leading to trauma-induced damage focuses on synaptic or ionic mechanisms, the possible role of direct intercellular communication via gap junctions has remained unexplored. Gap junctions connect directly the cytoplasms of coupled cells; hence, they offer a way to propagate stress signals from cell to cell. We investigated the contribution of gap junctional communication (GJC) to cell death using an in vitro trauma model. The impact injury, induced by a weight dropped on the distal CA1 area of organotypic hippocampal slices, results in glutamate-dependent cell loss. The gap junctional blockers carbenoxolone and octanol decreased significantly post-traumatic cell death, measured by propidium iodide staining over a 72 hr period after the impact. Dye coupling in the pyramidal layers was enhanced immediately after the injury and decreased over the following 24 hr. To determine whether specific connexins were involved in the spread of trauma-induced cell death, we used organotypic slices from connexin43 (Cx43) knock-out mice, as well as acute knock-outs by incubation with antisense oligodeoxynucleotides. Simultaneous knockdown of two neuronal connexins resulted in significant neuroprotection. Slices from the null-mutant Cx43 mice, as well as the acute Cx43 knockdown, also showed decreased cell death after the impact. The gap junctional blockers alleviated the trauma-induced impairment of synaptic function as measured by electrophysiological field potential recordings. These results indicate that GJC enhances the cellular vulnerability to traumatic injury. Hence, specific gap junctions could be a novel target to reduce injury and secondary damage to the brain and maximize recovery from trauma.