Role of brainstem cardiorespiratory neurons in SUDEP

癫痫的猝死(SUDEP)被定义为突然的、意想不到的和无法解释的 癫痫患者的死亡。在所有与癫痫相关的死亡中，SUDEP占8%至17%，呈上升趋势 在目前治疗无效的患者中，这一比例为50%。在所有神经系统疾病中，它排在第二位。 只为中风失去了多少生命年数。越来越多的证据支持呼吸暂停(呼吸停止)是 癫痫发作后的主要死因。据报道，呼吸暂停和氧气减饱和在 在惊厥发作期间和之后的患者百分比，以及在9例SUDEP病例中 视频脑电在癫痫监测单元(EMU)死亡时，均涉及发生呼吸骤停 终末期停搏前(MORTEMUS研究)。更好地了解以下项目涉及的关键流程 呼吸功能障碍和随后的SUDEP将使新的救援疗法的开发成为可能。 SUDEP发生在许多癫痫人群中。一种这样的弱势群体就是患有 SCN8A癫痫脑病(EE)，在NaV1.6钠通道上有功能突变的获得。 我们的小鼠模型含有在患有SUDEP的患者中发现的Scn8a突变，并产生许多 患者的临床症状，包括自发性全身性强直阵挛发作、呼吸暂停和 苏德普。使用这些临床相关的小鼠模型，我们将检验我们的中心假设SUDEP 在癫痫发作后由于持续的紧张性吸气活动而停止呼吸时发生，以及 呼吸恢复失败是由于心肺平衡受损。目标1：我们将确定 Bötzinger复合体(BötC)和后斜方核(RTN)脑干神经元在协调中的作用 应用光遗传学技术研究癫痫致呼吸暂停期间的吸气活动。目标2：癫痫患者处于危险之中 对于SUDEP来说，已经损害了中枢化疗敏感性。我们发现我们的SCN8A EE小鼠也受到了损害 中枢化疗敏感性。我们建议评估体内发育时间点的二氧化碳敏感性 SUDEP，并确定抑制钠通道(INA)电流是否可以恢复对二氧化碳的敏感性。我们会 测定RTN神经元的变化，以确定其CO2/H+敏感性、内源性兴奋性和INA电流。 最后，我们将使用shRNA在RTN中敲除NaV1.6，并评估其对体内二氧化碳的贡献。 敏感度和SUDEP。目的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。我们将在体内确定副交感神经心脏驱动 导致SUDEP，并确定INA抑制的效果。我们会用副交感神经做录音 并确定NaV1.6基因敲除对心动过缓和SUDEP的影响。这些 研究将显著影响我们目前对导致心肺疾病的心肺改变的理解 SUDEP，并可为预防SUDEP的新治疗靶点提供重要见解。

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.