Respiratory mechanisms of epilepsy with high risk of SUDEP

我们的长期目标是了解经络病变如何引起心肺疾病的癫痫。 癫痫的合并症和对猝死的易感性(SUDEP)是 与癫痫相关的死亡率。当癫痫患者因以下原因突然死亡时死亡被归类为SUDEP 未知的病理原因。假设SUDEP是由癫痫相关的心肺疾病引起的 最终导致死亡的功能障碍。然而，心脏和心脏的相对重要性和相互关系 SUDEP背后的呼吸因素尚不清楚，这对该领域的进展构成了重大障碍。 具有脑-心脏表达模式的离子通道基因突变，如KcNA1基因，有 被认为是SUDEP发作相关心律失常的分子原因。Kcna 1，a 人类癫痫基因与患者SUDEP风险增加相关，编码电压门控Kv1.1 钾通道α-在神经元和心肌细胞中表达的亚单位，它们在那里起控制作用 动作电位激发特性。KcNA1基因敲除(KO)小鼠是SUDEP的常用模型，因为它 概述了人类状况的关键方面，包括强直阵挛发作、发作性心动过缓和 过早死亡。鉴于Kcna_1KO小鼠的癫痫和心脏表型已被研究 在与SUDEP广泛相关的问题上，还没有探讨呼吸功能障碍的可能贡献。在……里面 初步实验中，我们使用体积描记术来识别几种类型的呼吸异常 Kcna1KO小鼠。在自发癫痫发作期间，KO小鼠表现出呼吸暂停，表明呼吸功能障碍 可能是导致他们猝死的主要因素。在发作间歇期，他们表现出 叹息后呼吸暂停频率和呼吸变异性的变化提示Kv1.1在维持 正常的呼吸生理学。 这个项目的目标是测试Kv1.1通道是正常呼吸所必需的假设 他们的缺乏会导致呼吸异常，从而增加SUDEP的风险。目标1将 测试Kcna1 KO小鼠癫痫发作期间呼吸功能障碍先于心动过缓的假设。目标2 将检验睡眠-觉醒状态有助于发作间歇期和发作期呼吸暂停发生的假设 Kcna1KO小鼠。为了在AIMS 1和AIMS 2中获取体内生物信号，我们建立了一种新的、最先进的 小鼠癫痫监测单元记录同步的脑-心脏-肌肉-呼吸活动。AIM 3将使用 Kv1.1通道在脑干呼吸中表达的免疫组织化学检验 他们的缺陷导致与癫痫有关的损害。这项研究将照亮十字路口 SUDEP的呼吸和心脏机制之间的关系，同时阐明Kv1.1的新作用 调节基础呼吸生理学的经络。这项研究的结果将影响 通过确定新的干预心肺策略，对SUDEP采取未来的预防措施。

Our long-term goal is to understand how channelopathies can cause epilepsy with cardiorespiratory comorbidities and susceptibility to sudden unexpected death in epilepsy (SUDEP), the leading cause of epilepsy-related mortality. Deaths are classified as SUDEP when people with epilepsy die suddenly for unknown pathological reasons. SUDEP is hypothesized to result from seizure-related cardiorespiratory dysfunction that culminates in death. However, the relative importance and interrelationship of cardiac and respiratory factors underlying SUDEP is unclear, posing a significant barrier to progress in the field. Mutations in ion channel genes with brain-heart expression patterns, such as the Kcna1 gene, have been proposed to be a molecular cause of seizure-related cardiac arrhythmias underlying SUDEP. Kcna1, a human epilepsy gene associated with increased SUDEP risk in patients, encodes voltage-gated Kv1.1 potassium channel α-subunits that are expressed in neurons and cardiomyocytes where they act to control action potential firing properties. The Kcna1 knockout (KO) mouse is an often utilized model of SUDEP since it recapitulates key aspects of the human condition, including tonic-clonic seizures, ictal bradycardia, and premature death. Whereas the epilepsy and cardiac phenotypes of Kcna1 KO mice have been studied extensively in relation to SUDEP, a possible contribution by respiratory dysfunction has not been explored. In preliminary experiments, we used plethysmography to identify several types of breathing abnormalities in Kcna1 KO mice. During spontaneous seizures, KO mice exhibited apneas, suggesting respiratory dysfunction may be the primary factor contributing to their sudden death. During interictal periods, they exhibited alterations in post-sigh apnea frequency and respiratory variability suggesting a role for Kv1.1 in maintaining normal respiratory physiology. The goal of this project is to test the hypothesis that Kv1.1 channels are required for normal respiratory physiology and that their absence leads to respiratory abnormalities that contribute to SUDEP risk. Aim 1 will test the hypothesis that respiratory dysfunction precedes bradycardia during seizures in Kcna1 KO mice. Aim 2 will test the hypothesis that sleep-wake status contributes to the occurrence of interictal and ictal apneas in Kcna1 KO mice. To acquire in vivo biosignals in aims 1 and 2, we have established a novel, state-of-the-art mouse epilepsy monitoring unit to record simultaneous brain-heart-muscle-respiratory activity. Aim 3 will use immunohistochemistry to test the hypothesis that Kv1.1 channels are expressed in brainstem respiratory networks and that their deficiency leads to seizure-related damage. This research will illuminate the crossroads between respiratory and cardiac mechanisms underlying SUDEP, while elucidating a novel role for Kv1.1 channels in regulating basal respiratory physiology. The results of this study will impact the development of future preventative measures for SUDEP by identifying new cardiorespiratory strategies for intervention.