Role of brainstem cardiorespiratory neurons in SUDEP

脑干心肺神经元在 SUDEP 中的作用

• 批准号: 10617589
• 负责人: MANOJ K PATEL
• 金额: $ 4.49万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2026-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617589
• 关键词: Apnea; Bradycardia; Brain Stem; Breathing; Carbon Dioxide; Cardiac; Cause of Death; Cell Nucleus; Cessation of life; Clinical; Complex; Development; Electroencephalography; Epilepsy; Failure; Heart Arrest; Homeostasis; Impairment; Lead; Monitor; Motor Seizures; Mus; Mutation; Neurologic; Neurons; Oxygen; Patients; Persons; Population; Process; Recovery; Reporting; Respiration Disorders; Risk; Role; SCN8A gene; Seizures; Sodium Channel; Stroke; Symptoms; Techniques; Testing; Time; Tonic - clonic seizures; Vulnerable Populations; clinically relevant; epileptic encephalopathies; gain of function mutation; in vivo; ineffective therapies; insight; knock-down; mouse model; new therapeutic target; novel; novel therapeutics; optogenetics; patient population; prevent; respiratory; small hairpin RNA; sudden unexpected death in epilepsy; years of life lost

Sudden Unexpected Death in Epilepsy (SUDEP) is defined as the sudden, unexpected, and unexplained death of a person with epilepsy. SUDEP accounts for between 8 and 17% of all epilepsy-related deaths, rising to 50% in patients for which current therapies are ineffective. Amongst all neurological conditions, it is second only to stroke for number of life-years lost. Increasing evidence supports apnea (breathing cessation) as the primary cause of death following a seizure. Apnea and oxygen desaturation have been reported in a large percentage of patients during and after convulsive seizures, and of the 9 SUDEP cases that were monitored by video-EEG in epilepsy monitoring units (EMUs) at the time of death, all involved respiratory arrest occurring before terminal asystole (MORTEMUS study). A better understanding of the key processes involved in respiratory dysfunction and subsequent SUDEP would allow for the development of novel rescue therapies. SUDEP occurs across numerous epilepsy populations. One such vulnerable population are patients with SCN8A epileptic encephalopathy (EE), who have a gain of function mutation in the NaV1.6 sodium channel. Our mice models harbor Scn8a mutations identified in patients that suffered SUDEP, and produce many of the clinical symptoms of the patients, including spontaneous generalized tonic-clonic seizures, apnea, and SUDEP. Using these clinically relevant mice models we will test our CENTRAL HYPOTHESIS that SUDEP occurs when breathing ceases after a seizure, as a result of constant tonic inspiratory activity, and failure of breathing recovery is due to impaired cardiorespiratory homeostasis. AIM 1: We will determine the role of the Bötzinger complex (BötC) and retrotrapezoid nucleus (RTN) brainstem neurons on coordinating inspiratory activity during seizure-induced apnea using optogenetic techniques. AIM 2: Epilepsy patients at risk for SUDEP have impaired central chemosensitivity. We show that our SCN8A EE mice also have impaired central chemosensitivity. We propose to assess in vivo CO2-sensitivity at developmental time points leading up to SUDEP and determine if inhibition of sodium channel (INa) currents can rescue CO2-sensitivity. We will determine changes in RTN neurons to determine their CO2/H+-sensitivity, intrinsic excitability, and INa currents. Finally, we will use shRNA to knockdown NaV1.6 in the RTN and assess its contribution to in vivo CO2- sensitivity and SUDEP. AIM 3: Impaired cardiac control is a contributor of SUDEP, and we find that bradycardia occurs immediately prior to SUDEP. We will determine in vivo parasympathetic cardiac drive leading up to SUDEP and determine effects of INa inhibition. We will make recordings from parasympathetic cardiovagal neurons and determine the effects of NaV1.6 knockdown on bradycardia and SUDEP. These studies will significantly impact our current understanding of the cardiorespiratory alterations that lead to SUDEP and could provide important insight into novel therapeutic targets to prevent SUDEP.

癫痫猝死（SUDEP）被定义为突然的、意外的、无法解释的 癫痫患者的死亡占所有癫痫相关死亡的 8% 至 17%，并且这一数字还在上升。 在目前治疗无效的患者中，这种情况占到 50%。 在所有神经系统疾病中，它位居第二。 越来越多的证据支持呼吸暂停（呼吸停止）是导致中风死亡的原因。 据报道，癫痫发作和氧饱和度下降是导致死亡的主要原因。 惊厥发作期间和之后的患者百分比，以及 9 例 SUDEP 病例中由 死亡时癫痫监测装置 (EMU) 中的视频脑电图，全部涉及呼吸停止 终末期心搏停止之前（MORTEMUS 研究）更好地了解涉及的关键过程。 呼吸功能障碍和随后的 SUDEP 将有助于开发新的救援疗法。 SUDEP 发生在许多癫痫人群中，其中之一就是患有以下疾病的患者。 SCN8A 癫痫性脑病 (EE)，NaV1.6 钠通道功能获得性突变。 我们的小鼠模型携带在患有 SUDEP 的患者中发现的 Scn8a 突变，并产生许多 患者的临床症状，包括自发性全身强直阵挛发作、呼吸暂停和 SUDEP。使用这些临床相关的小鼠模型，我们将测试我们的中心假设：SUDEP 当癫痫发作后由于持续的强直吸气活动导致呼吸停止时发生，并且 呼吸恢复失败是由于心肺稳态受损所致 目的 1：我们将确定。 Bötzinger 复合体 (BötC) 和后梯形核 (RTN) 脑干神经元在协调中的作用 使用光遗传学技术检测癫痫发作引起的呼吸暂停期间的吸气活动目标 2：处于危险中的癫痫患者。 SUDEP 的中枢化学敏感性受损，我们的 SCN8A EE 小鼠也受损。 我们建议在发育时间点评估体内二氧化碳敏感性。 进行 SUDEP 并确定抑制钠通道 (INa) 电流是否可以挽救 CO2 敏感性。 确定 RTN 神经元的变化，以确定其 CO2/H+ 敏感性、内在兴奋性和 INa 电流。 最后，我们将使用 shRNA 敲低 RTN 中的 NaV1.6，并评估其对体内 CO2- 的贡献。 敏感性和 SUDEP 目标 3：心脏控制受损是 SUDEP 的一个因素，我们发现 心动过缓发生在 SUDEP 之前，我们将确定体内副交感神经心脏驱动。 导致 SUDEP 并确定 INa 抑制的效果，我们将从副交感神经进行记录。 心脏迷走神经元并确定 NaV1.6 敲低对心动过缓和 SUDEP 的影响。 研究将极大地影响我们目前对导致心肺功能改变的理解 SUDEP 可以为预防 SUDEP 的新治疗靶点提供重要见解。