Potassium channel gene therapy can prevent neuron death resulting from necrotic and apoptotic insults
Potassium channel gene therapy can prevent neuron death resulting from necrotic and apoptotic insults
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DOI：
10.1046/j.1471-4159.2003.01880.x
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发表时间：
2003-09-01
影响因子：
4.7
通讯作者：
Sapolsky, RM
中科院分区：
文献类型：
--
作者：
Lee, AL;Dumas, TC;Sapolsky, RM
坏死性损伤如癫痫发作是兴奋性毒性的。从逻辑上讲，通过增加外向传导钾通道电流的膜超极化应该减弱过度兴奋并增强神经元存活。因此，我们通过病毒载体在培养的海马神经元中过表达小电导钙激活（SK 2）或电压门控（Kv1.1）通道。我们发现，SK 2或Kv1.1不仅保护红藻氨酸或谷氨酸兴奋毒性，但也增加了生存后氰化钠或星形孢菌素。在体内过度表达任一通道的齿状回减少红藻氨酸诱导的CA3病变。在海马脑片中，红藻氨酸诱导的颗粒细胞兴奋性的增加被过度表达的任一通道，这表明这些通道在过度兴奋发挥其保护作用。理解转基因过度表达单独引起的功能紊乱也很重要。在没有损伤的情况下，Kv1.1的过度表达，但不是SK 2，降低了齿状回颗粒细胞的基线兴奋性。此外，虽然在Morris水迷宫中的空间获取过程中没有观察到任何通道的过表达的行为障碍，但过表达SK 2而不是Kv1.1的动物在训练后表现出记忆缺陷。这种差异提出了一种可能性，即这些通道子类型的保护方式可能不同。随着进一步的发展，钾通道载体可能是一种有效的预防坏死性损伤的策略。
Necrotic insults such as seizure are excitotoxic. Logically, membrane hyperpolarization by increasing outwardly conducting potassium channel currents should attenuate hyperexcitation and enhance neuron survival. Therefore, we overexpressed a small-conductance calcium-activated (SK2) or voltage-gated (Kv1.1) channel via viral vectors in cultured hippocampal neurons. We found that SK2 or Kv1.1 protected not only against kainate or glutamate excitotoxicity but also increased survival after sodium cyanide or staurosporine. In vivo overexpression of either channel in dentate gyrus reduced kainate-induced CA3 lesions. In hippocampal slices, the kainate-induced increase in granule cell excitability was reduced by overexpression of either channel, suggesting that these channels exert their protective effects during hyperexcitation. It is also important to understand any functional disturbances created by transgene overexpression alone. In the absence of insult, overexpression of Kv1.1, but not SK2, reduced baseline excitability in dentate gyrus granule cells. Furthermore, while no behavioral disturbances during spatial acquisition in the Morris water maze were observed with overexpression of either channel, animals overexpressing SK2, but not Kv1.1, exhibited a memory deficit post-training. This difference raises the possibility that the means by which these channel subtypes protect may differ. With further development, potassium channel vectors may be an effective pre-emptive strategy against necrotic insults.