Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner
Developmental febrile seizures modulate hippocampal gene expression of hyperpolarization-activated channels in an isoform- and cell-specific manner
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DOI：
10.1523/jneurosci.22-11-04591.2002
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发表时间：
2002-06-01
影响因子：
5.3
通讯作者：
Baram, TZ
中科院分区：
文献类型：
--
作者：
Brewster, A;Bender, RA;Baram, TZ
热性惊厥除了是人类发育过程中最常见的癫痫类型外，还可能导致随后的边缘叶癫痫的发生。我们之前的工作表明，未成熟大鼠模型中长时间的实验性热性惊厥会长期增加海马的兴奋性，从而增强对未来癫痫发作的易感性。这些深刻的促癫痫发生变化的机制不需要细胞死亡，并且与超极化激活的去极化电流（I-H）的长期缓慢动力学相关。在这里，我们发现这些癫痫发作调节编码这种电流的基因的表达，即超极化激活的环核苷酸门控通道（HCN）：在表达多种HCN亚型的CA1神经元中，癫痫发作诱导HCN1 mRNA协调减少和HCN2表达增强，从而改变神经元HCN表型。癫痫发作引起的 HCN2 表达增强除了 CA1 之外还涉及 CA3，而对于 HCN4，任一海马区域的癫痫发作均未改变 mRNA 表达。 HCN 的这种亚型和区域特异性转录调节需要神经元活动而不是单独的高热，与癫痫发作持续时间相关，并且有利于慢动力学 HCN2 编码通道的形成。总之，这些数据证明了发育性癫痫发作对 HCN 分子的新颖的、活性依赖性的转录调节。这些变化导致特定海马神经元群的 HCN 表型发生长期改变，对海马网络的兴奋性产生深远影响。
Febrile seizures, in addition to being the most common seizure type of the developing human, may contribute to the generation of subsequent limbic epilepsy. Our previous work has demonstrated that prolonged experimental febrile seizures in the immature rat model increased hippocampal excitability long term, enhancing susceptibility to future seizures. The mechanisms for these profound proepileptogenic changes did not require cell death and were associated with long-term slowed kinetics of the hyperpolarization-activated depolarizing current (I-H). Here we show that these seizures modulate the expression of genes encoding this current, the hyperpolarization-activated, cyclic nucleotide-gated channels (HCNs): In CA1 neurons expressing multiple HCN isoforms, the seizures induced a coordinated reduction of HCN1 mRNA and enhancement of HCN2 expression, thus altering the neuronal HCN phenotype. The seizure-induced augmentation of HCN2 expression involved CA3 in addition to CA1, whereas for HCN4, mRNA expression was not changed by the seizures in either hippocampal region. This isoform- and region-specific transcriptional regulation of the HCNs required neuronal activity rather than hyperthermia alone, correlated with seizure duration, and favored the formation of slow-kinetics HCN2-encoded channels. In summary, these data demonstrate a novel, activity-dependent transcriptional regulation of HCN molecules by developmental seizures. These changes result in long-lasting alteration of the HCN phenotype of specific hippocampal neuronal populations, with profound consequences on the excitability of the hippocampal network.