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 of Kcna1, 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 floxed Kcna1 mouse which we crossed to mice with the Synapsin1-Cre transgene, which selectively deletes Kcna1 in most neurons. Molecular analyses confirmed neuron-specific Kcna1 deletion 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.

中文翻译：

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神经元特异性Kv1.1不足足以引起癫痫，过早死亡和心肺功能失调。

癫痫猝死（SUDEP）是癫痫相关死亡率的主要原因，但涉及的确切细胞基质仍然难以捉摸。已经提出在脑和心脏中共表达的癫痫相关离子通道基因作为SUDEP候选基因，因为它们提供了癫痫发作和致命性心律不齐之间的单一统一链接。在这里，我们生成了一个条件敲除（cKO）小鼠，它具有神经元特异性缺失Kcna1（一种与脑心共表达的SUDEP相关基因），以测试癫痫诱发的心律不齐和SUDEP是否需要在小鼠中不存在Kv1.1大脑和心脏，或者神经元消融是否足够。为了获得cKO小鼠，我们开发了一种Floxed Kcna1小鼠，将其与带有Synapsin1-Cre转基因的小鼠杂交，该基因选择性地删除了大多数神经元中的Kcna1。分子分析证实了cKO小鼠中神经元特异性Kcna1缺失以及相应的Kv1.1丢失，但小脑中Synapsin1-Cre并未高度表达。生存研究和脑电图，心电图和体积描记记录表明，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。cKO小鼠的心率变异性（HRV）升高，白天达到高峰，表明昼夜HRV模式被干扰为SUDEP生物标记。cKO小脑中残留的Kv1.1表达表明，它可能在调节发作性心肺功能不全和SUDEP风险中起意想不到的作用。