Prevention of Seizure-Induced Sudden Death by Stimulating Serotonergic Signaling

项目摘要/摘要 癫痫患者发生癫痫猝死(SUDEP)的风险高出20倍以上 而不是普通人群中的死亡。临床和动物研究表明，癫痫发作诱导的呼吸道 逮捕是导致死亡的首要事件。大脑中5-羟色胺(5-HT)水平的增加减少了癫痫发作- 诱发惊厥模型的诱导呼吸骤停。然而，目前尚不清楚是否增强5-羟色胺神经- 传递对自发性癫痫(癫痫)致痫性猝死的保护作用 以及在诱发性和自发性癫痫发作中，哪个5-羟色胺回路参与了这种猝死 模特们。这些知识上的差距严重阻碍了预防患者SUDEP的治疗方法。 长期目标是制定有效的预防战略，使用有针对性的方法来预防SUDEP 特定的SUDEP机制。这项建议的总体目标是：(1)确定5-羟色胺的疗效。 抑制癫痫猝死的增强剂和(2)阐明涉及的5-羟色胺回路 动物模型中的机制，特别是在广泛使用的人类Drave综合症(一种 癫痫)，表现为自发性癫痫发作，癫痫导致猝死的比率很高。中环 假说认为，增强的5-羟色胺信号可防止癫痫导致的猝死，而5-羟色胺中缝- DBA/1和Dravet小鼠的这种猝死与杏仁核回路有关。这项提议的理由是 5-羟色胺增强剂和5-羟色胺神经元环路临床前疗效的测定 癫痫诱发猝死的机制可能提供一个强有力的科学框架，通过 可以开发出针对人类SUDEP的策略。核心假设将在以下两个方面得到检验 具体目的：1)确定增强5-羟色胺神经递质对癫痫的保护作用 DBA/1和Dravet小鼠猝死；2)阐明5-羟色胺从中缝核团到杏仁核的回路是如何- LA可改善DBA/1和Dravet小鼠癫痫诱发的猝死。我们将采用SIMUL-2的组合 同时视频脑电/心电/体积描记监测、电生理学、药理学和细胞类型特异性 技术(光遗传学和DREADD)来执行这些目标的工作。这项拟议的研究是徒劳的- 这是因为它定义了一种新的5-羟色胺回路机制，利用光遗传学- 动物模型中的ICS和DREADD，特别是在人类疾病模型中，这在概念上可能会 对SUDEP的病理生理机制的认识。拟议的工作意义重大，因为 预期的结果可能会促进有针对性的药物和神经刺激干预 SUDEP以挽救高危患者的生命。

PROJECT SUMMARY/ABSTRACT The risk of sudden unexpected death in epilepsy (SUDEP) in patients with epilepsy is more than 20-fold higher than that of death in the general population. Clinical and animal studies show that seizure-induced respiratory arrest is the primary event leading to death. Increased serotonin (5-HT) levels in the brain reduce seizure- induced respiratory arrest in provoked seizure models. However, it is unclear whether enhancing 5-HT neuro- transmission exerts protective effects on seizure-induced sudden death in spontaneous seizure (epilepsy) models and which 5-HT circuitry is involved in this sudden death in both provoked and spontaneous seizure models. These gaps in knowledge have significantly hindered the therapeutics to prevent SUDEP in patients. The long-term goal is to foster effective prevention strategies against SUDEP using approaches targeted to specific SUDEP mechanisms. The overall objectives of this proposal are to (1) determine the efficacy of 5-HT- enhancing agents in suppressing seizure-induced sudden death and (2) elucidate the involved 5-HT circuitry mechanisms in animal models, especially in a widely-used mouse model of human Dravet syndrome (a type of epilepsy) that displays spontaneous seizures with a high rate of seizure-induced sudden death. The central hypothesis is that enhanced 5-HT signaling prevents seizure-induced sudden death, and that the 5-HT raphe- amygdala circuitry is involved in this sudden death in DBA/1 and Dravet mice. The rationale for this proposal is that a determination of preclinical therapeutic efficacy of 5-HT-enhancing agents and 5-HT neuronal circuitry mechanisms in seizure-induced sudden death is likely to offer a strong scientific framework by which new strategies against human SUDEP can be developed. The central hypothesis will be tested in the following two specific aims: 1) Determine the protective effects of enhancing 5-HT neurotransmission on seizure-induced sudden death in DBA/1 and Dravet mice; and 2) Elucidate how 5-HT circuitry from raphe nuclei to the amygda- la modifies seizure-induced sudden death in DBA/1 and Dravet mice. We will employ a combination of simul- taneous video EEG/ECG/plethysmography monitoring, electrophysiology, pharmacology and cell-type specific technologies (optogenetics and DREADDs) to perform the work in these aims. The proposed research is inno- vative because it defines a novel 5-HT circuitry mechanism of seizure-induced sudden death using optogenet- ics and DREADDs in animal models, especially in a human disease model, which could conceptually advance the knowledge on the pathophysiological mechanisms of SUDEP. The proposed work is significant because the expected outcomes will potentially foster targeted pharmacologic and neurostimulatory interventions of SUDEP to save lives of at-risk patients.