Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy
Progressive dendritic HCN channelopathy during epileptogenesis in the rat pilocarpine model of epilepsy
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DOI：
10.1523/jneurosci.3605-07.2007
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发表时间：
2007-11-21
影响因子：
5.3
通讯作者：
Poolos, Nicholas P.
中科院分区：
文献类型：
--
作者：
Jung, Sangwook;Jones, Terrance D.;Poolos, Nicholas P.
离子通道病在由遗传原因引起的人类癫痫中发挥着重要作用，并且推测离子通道病也会在中枢神经系统受到后天性损伤后发生在癫痫中。在癫痫动物模型中诱导癫痫持续状态（SE）后，离子通道功能会发生获得性改变，但尚不清楚它们与自发性癫痫发作的关系如何。我们结合视频脑电图 (VEEG) 记录检查了 CA1 海马锥体神经元中超极化激活阳离子 (HCN) 通道的特性，以监测大鼠毛果芸香碱癫痫模型中自发性癫痫发作的发展。我们的结果表明，树突状 HCN 通道在毛果芸香碱后 1 周的急性时间点显着下调，通道表达丧失，电压依赖性激活超极化。当癫痫在慢性期确立时，这种下调逐渐增加。令人惊讶的是，急性期的 VEEG 记录显示，相当一部分动物已经出现反复癫痫发作。用苯巴比妥抑制这些癫痫发作逆转了 I-h（HCN 通道产生的电流）电压依赖性的变化，但不影响 HCN 通道表达的丧失。这些结果表明 SE 后 HCN 通道下调有两种机制，一种依赖于复发性癫痫发作，另一种独立于复发性癫痫发作。树突HCN通道功能的这种早期和渐进的下调增加了神经元的兴奋性，并且可能与癫痫发生和癫痫状态的维持过程相关。
Ion channelopathy plays an important role in human epilepsy with a genetic cause and has been hypothesized to occur in epilepsy after acquired insults to the CNS as well. Acquired alterations of ion channel function occur after induction of status epilepticus (SE) in animal models of epilepsy, but it is unclear how they correlate with the onset of spontaneous seizures. We examined the properties of hyperpolarization-activated cation (HCN) channels in CA1 hippocampal pyramidal neurons in conjunction with video-EEG (VEEG) recordings to monitor the development of spontaneous seizures in the rat pilocarpine model of epilepsy. Our results showed that dendritic HCN channels were significantly downregulated at an acute time point 1 week postpilocarpine, with loss of channel expression and hyperpolarization of voltage-dependent activation. This downregulation progressively increased when epilepsy was established in the chronic period. Surprisingly, VEEG recordings during the acute period showed that a substantial fraction of animals were already experiencing recurrent seizures. Suppression of these seizures with phenobarbital reversed the change in the voltage dependence of I-h, the current produced by HCN channels, but did not affect the loss of HCN channel expression. These results suggest two mechanisms of HCN channel downregulation after SE, one dependent on and one independent of recurrent seizures. This early and progressive downregulation of dendritic HCN channel function increases neuronal excitability and may be associated with both the process of epileptogenesis and maintenance of the epileptic state.