Oscar Langendorff Institute of Physiology, University of Rostock, Gertrudenstrasse 9, 18057 Rostock, Germany.
Neurobiol Dis. 2012 Jan;45(1):337-47. doi: 10.1016/j.nbd.2011.08.019. Epub 2011 Aug 25.
Hippocampal CA1 pyramidal neurons generate an after-hyperpolarization (AHP) whose medium component is thought to be generated by small-conductance Ca(2+)-activated K(+) channels (SK channels). Neuronal excitability is increased in epilepsy, and the AHP in turn is fundamentally involved in regulation of cellular excitability. We therefore investigated the involvement of the SK channel-mediated AHP in controlling cell and network excitability in the pilocarpine model epilepsy. Both acutely isolated CA1 pyramidal cells and isolated hippocampal slices were investigated in terms of the impact of SK channel-mediated AHP on hyperexcitability. Our findings show that pilocarpine-treated chronically epileptic rats exhibit significantly reduced SK channel-mediated hyperpolarizing outward current which was accompanied by a significant decrease in the somatic AHP. Paradoxically, inhibiting SK channels strongly exacerbated 0-Mg(2+)-induced epileptiform activity in slices from pilocarpine-treated animals, while having a significantly smaller effect in control tissue. This suggests that in chronically epileptic tissue, network excitability very critically depends on the remaining SK-channel mediated AHP. Additional real-time RT-PCR and semiquantitative Western blot experiments revealed that both the SK2 channel transcript and protein were significantly downregulated in the epileptic CA1 region. We conclude that SK2 channels are down-regulated in chronic epilepsy underlying the impaired SK channel function in CA1 pyramidal cells, and a further reduction of the remaining critical mass of SK channels results in an acute network decompensation.
海马 CA1 锥体神经元产生超极化后电位（AHP），其中间成分被认为是由小电导钙激活钾（SK）通道产生的。癫痫时神经元兴奋性增加，AHP 反过来又从根本上参与调节细胞兴奋性。因此，我们研究了 SK 通道介导的 AHP 在控制匹罗卡品癫痫模型中细胞和网络兴奋性中的作用。急性分离的 CA1 锥体神经元和分离的海马切片都研究了 SK 通道介导的 AHP 对过度兴奋的影响。我们的研究结果表明，匹罗卡品治疗的慢性癫痫大鼠表现出明显减少的 SK 通道介导的超极化外向电流，同时体细胞 AHP 明显减少。矛盾的是，抑制 SK 通道强烈加剧了来自匹罗卡品治疗动物的 0-Mg（2+）诱导的癫痫样活动，而在对照组织中则有明显较小的作用。这表明在慢性癫痫组织中，网络兴奋性非常依赖于剩余的 SK 通道介导的 AHP。额外的实时 RT-PCR 和半定量 Western blot 实验表明，癫痫 CA1 区的 SK2 通道转录本和蛋白均显著下调。我们的结论是，SK2 通道在慢性癫痫中下调，导致 CA1 锥体神经元中 SK 通道功能受损，剩余关键质量的 SK 通道进一步减少导致急性网络失代偿。
