Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS)
Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS)
复制标题
内侧颞叶癫痫和海马硬化 (MTLE-HS) 患者海马超极化激活的环核苷酸门控通道 (HCN) 的下调
DOI：
10.1002/hipo.23219
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发表时间：
2020-06-16
期刊：
影响因子：
3.5
通讯作者：
Zhou, Liemin
中科院分区：
文献类型：
--
作者：
Lin, Wanrong;Qin, Jiaming;Zhou, Liemin
HCN离子通道表达的变化导致I(h)功能和神经元兴奋性的变化被认为是人类癫痫发生的可能机制。以往热性惊厥和颞叶癫痫的动物研究中，不同时间点、大脑不同部位的HCN1和HCN2通道表达变化并不一致，提示涉及HCN的转录障碍在癫痫发生过程中发挥着至关重要的作用。因此，我们的目的是评估内侧颞叶癫痫伴海马硬化（MTLE-HS）患者中 HCN 通道的转录调控。这项研究包括 8 名非海马硬化患者和 40 名 MTLE-HS 患者。通过qRT-PCR评估HCN通道的mRNA表达，并通过Western blotting定量分析蛋白表达。通过免疫荧光探索海马 HCN 通道的亚细胞定位。我们证明，与 MTLE-HS 患者相比，对照组 HCN1 和 HCN2 的 mRNA 和蛋白表达下调。在海马CA1/CA4亚区和GCL中，MTLE-HS患者除了神经元大量减少外，神经元细胞膜上HCN1和HCN2的表达也下调。这些发现提示MTLE-HS中HCN通道表达下调，说明MTLE-HS患者慢性癫痫过程中海马HCN通道下降导致I(h)电流密度和功能下调，从而降低抑制作用，增加神经元兴奋性，最终引起神经元电活动紊乱。
Changes in the expression of HCN ion channels leading to changes inI(h)function and neuronal excitability are considered to be possible mechanisms involved in epileptogenesis in kinds of human epilepsy. In previous animal studies of febrile seizures and temporal lobe epilepsy, changes in the expression of HCN1 and HCN2 channels at different time points and in different parts of the brain were not consistent, suggesting that transcriptional disorders involving HCNs play a crucial role in the epileptogenic process. Therefore, we aimed to assess the transcriptional regulation of HCN channels in Medial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. This study included eight nonhippocampal sclerosis patients and 40 MTLE-HS patients. The mRNA expression of HCN channels was evaluated by qRT-PCR, while the protein expression was quantitatively analyzed by Western blotting. The subcellular localization of HCN channels in the hippocampus was explored by immunofluorescence. We demonstrated that the mRNA and protein expression of HCN1 and HCN2 are downregulated in controls compared to that in MTLE-HS patients. In the hippocampal CA1/CA4 subregion and GCL, in addition to a large decrease in neurons, the expression of HCN1 and HCN2 on neuronal cell membranes was also downregulated in MTLE-HS patients. These findings suggest that the expression of HCN channels are downregulated in MTLE-HS, which indicates that the decline in HCN channels in the hippocampus during chronic epilepsy in MTLE-HS patients leads to the downregulation ofI(h)current density and function, thereby reducing the inhibitory effect and increasing neuronal excitability and eventually causing disturbances in the electrical activity of neurons.