Neuron-specific Kv1.1 deficiency is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation.
Neuron-specific Kv1.1 deficiency is sufficient to cause epilepsy, premature death, and cardiorespiratory dysregulation.
复制标题
神经元特异性 Kv1.1 缺陷足以导致癫痫、过早死亡和心肺失调。
DOI：
10.1016/j.nbd.2020.104759
复制
发表时间：
2020
影响因子：
6.1
通讯作者：
Glasscock,Edward
中科院分区：
文献类型：
--
作者：
Trosclair,Krystle;Dhaibar,HemanginiA;Gautier,NicoleM;Mishra,Vikas;Glasscock,Edward
癫痫猝死（SUDEP）是癫痫相关死亡的主要原因，但涉及的确切细胞基质仍然难以捉摸。癫痫相关的离子通道基因在脑和心脏中共表达，已被提出作为SUDEP候选基因，因为它们提供了癫痫发作和致命性心律失常之间的单一统一联系。在这里，我们产生了一个条件性基因敲除（cKO）小鼠与神经元特异性缺失Kcna 1，SUDEP相关基因与脑-心共表达，以测试是否心脏病引起的心律失常和SUDEP需要在大脑和心脏的Kv1.1的情况下，或是否在神经元消融是足够的。为了获得cKO小鼠，我们开发了一种克隆的Kcna 1小鼠，我们将其与具有Synapsin 1-Cre转基因的小鼠杂交，该转基因选择性地删除大多数神经元中的Kcna 1。分子分析证实了cKO小鼠中神经元特异性Kcna 1缺失和相应的Kv1.1缺失，但小脑中突触蛋白1-Cre表达不高。存活研究和脑电图、心电图和体积描记记录显示，cKO小鼠表现出过早死亡、癫痫和心肺功能失调，但程度低于整体敲除小鼠。cKO小鼠的心率变异性（HRV）增加，白天达到峰值，表明昼夜HRV模式紊乱是SUDEP生物标志物。cKO小脑中残留的Kv1.1表达表明其可能在调节发作性心肺功能障碍和SUDEP风险中发挥意想不到的作用。这项工作证明了具有脑-心表达模式的通道病可以单独通过脑驱动机制增加死亡风险而没有功能受损的心脏的原理，加强癫痫控制作为SUDEP预防的主要临床策略。
Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy-related mortality, but the precise cellular substrates involved remain elusive. Epilepsy-associated ion channel genes with co-expression in brain and heart have been proposed as SUDEP candidate genes since they provide a singular unifying link between seizures and lethal cardiac arrhythmias. Here, we generated a conditional knockout (cKO) mouse with neuron-specific deletion ofKcna1, a SUDEP-associated gene with brain-heart co-expression, to test whether seizure-evoked cardiac arrhythmias and SUDEP require the absence of Kv1.1 in both brain and heart or whether ablation in neurons is sufficient. To obtain cKO mice, we developed a floxedKcna1mouse which we crossed to mice with the Synapsin1-Cre transgene, which selectively deletesKcna1in most neurons. Molecular analyses confirmed neuron-specificKcna1deletion in cKO mice and corresponding loss of Kv1.1 except in cerebellum where Synapsin1-Cre is not highly expressed. Survival studies and electroencephalography, electrocardiography, and plethysmography recordings showed that cKO mice exhibit premature death, epilepsy, and cardiorespiratory dysregulation but to a lesser degree than global knockouts. Heart rate variability (HRV) was increased in cKO mice with peaks during daytime suggesting disturbed diurnal HRV patterns as a SUDEP biomarker. Residual Kv1.1 expression in cKO cerebellum suggests it may play an unexpected role in regulating ictal cardiorespiratory dysfunction and SUDEP risk. This work demonstrates the principle that channelopathies with brain-heart expression patterns can increase death risk by brain-driven mechanisms alone without a functionally compromised heart, reinforcing seizure control as a primary clinical strategy for SUDEP prevention.