Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus.
Rapid loss of dendritic HCN channel expression in hippocampal pyramidal neurons following status epilepticus.
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DOI：
10.1523/jneurosci.1148-11.2011
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发表时间：
2011-10-05
期刊：
影响因子：
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通讯作者：
Poolos NP
中科院分区：
文献类型：
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作者：
Jung S;Warner LN;Pitsch J;Becker AJ;Poolos NP
癫痫与超极化激活的环核苷酸门控（HCN）离子通道的表达和功能丧失有关。以前，我们表明，损失HCN通道介导的电流（Ih）发生在海马CA1区锥体神经元的树突后，匹罗卡品诱导癫痫持续状态（SE），伴随着损失HCN 1通道蛋白表达。然而，SE后HCN 1通道丢失的确切发作和机制基础尚不清楚，特别是它是否在自发性复发性癫痫发作之前发生，并可能导致癫痫发生或癫痫状态的发展。在这里，我们发现，损失的Ih和HCN 1通道表达开始在SE后一个小时内，并涉及树突HCN 1通道内化，延迟损失的蛋白质表达，后来下调的mRNA表达的顺序过程。我们还发现，在体外SE模型再现的树突状Ih的快速损失，表明这种现象是不特定的在体内SE。总之，这些结果表明，HCN 1通道病开始迅速，并持续后SE，涉及转录和非转录机制，并可能是癫痫发生的早期贡献者。
Epilepsy is associated with loss of expression and function of hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channels. Previously we showed that loss of HCN channel-mediated current (Ih) occurred in the dendrites of CA1 hippocampal pyramidal neurons after pilocarpine-induced status epilepticus (SE), accompanied by loss of HCN1 channel protein expression. However, the precise onset and mechanistic basis of HCN1 channel loss post-SE was unclear, particularly whether it preceded the onset of spontaneous recurrent seizures and could contribute to epileptogenesis, or development of the epileptic state. Here we found that loss of Ih and HCN1 channel expression begins within an hour after SE, and involves sequential processes of dendritic HCN1 channel internalization, delayed loss of protein expression, and later downregulation of mRNA expression. We also found that an in vitro SE model reproduced the rapid loss of dendritic Ih, demonstrating that this phenomenon was not specific to in vivo SE. Together, these results show that HCN1 channelopathy begins rapidly and persists after SE, involves both transcriptional and non-transcriptional mechanisms, and may be an early contributor to epileptogenesis.