Role of Central 5-HT Transmission in Respiratory Arrest Induced by Seizures

描述(申请人提供)：癫痫突发意外死亡(SUDEP)是癫痫的一种破坏性并发症，与全身性癫痫发作有关。癫痫诱发的呼吸和心脏抑制被认为是SUDEP的关键机制，但目前还没有有效的治疗方法，部分原因是缺乏类似人类SUDEP的动物模型。最近，有报道称DBA的两个亚系(DBA/1和DBA/2)小鼠表现出呼吸骤停，导致全身惊厥发作后的心脏骤停，就像在人类中观察到的那样。有趣的是，系统地给予一种提高突触5-羟色胺(5-HT)水平的药物显著减少了DBA小鼠由全身性癫痫发作引起的呼吸停止，这表明5-羟色胺神经传递可能在SUDEP中发挥重要作用。最近的一份回顾性临床报告表明，服用类似5-羟色胺类药物的患者癫痫引起的呼吸抑制有所减轻。然而，5-羟色胺可能作用于减少癫痫引起的呼吸骤停的神经网络部位目前尚不清楚。我们假设延髓呼吸中枢5-羟色胺神经传递不足导致DBA/1小鼠全身性惊厥引起的呼吸骤停。这一假设基于以下观察结果。首先，延髓呼吸中枢在呼吸中具有广泛的作用，而5-羟色胺是调节呼吸节律的关键调节剂。其次，在其他健康的人中，髓质脑损伤会导致猝死。第三，延髓中5-羟色胺神经传递的缺陷在婴儿猝死综合征中起到了致病作用，这种疾病被认为与SUDEP具有相似的病理生理学。最后，在DBA亚系小鼠的脑干(包括延髓呼吸中枢)中发现了几种5-羟色胺受体亚型的异常。我们将在DBA/1小鼠身上测试这一假设，因为DBA/1小鼠比DBA/2小鼠(7天)更容易出现呼吸骤停几周。本研究的具体目的是：1)确定增强脑干5-羟色胺神经递质对DBA/1小鼠全身性惊厥所致呼吸骤停的影响；2)确定延髓呼吸中枢前Botzinger复合体中的哪些5-羟色胺受体参与惊厥所致的呼吸骤停。拟议研究的成功实施不仅将为SUDEP的机制提供重要的线索，而且还将为这一毁灭性癫痫事件的治疗提供有用的信息。 公共卫生相关性：癫痫猝死(SUDEP)是与癫痫相关的主要死亡原因。SUDEP的病理生理学机制知之甚少，目前缺乏针对该疾病的治疗和预防治疗。本研究的目的是阐明SUDEP的神经回路机制，以促进有效治疗的发展。

DESCRIPTION (provided by applicant): Sudden unexpected death in epilepsy (SUDEP) is a devastating complication of epilepsy associated with generalized seizures. Seizure-induced respiratory and cardiac depression are proposed to be key mechanisms underlying SUDEP, but effective treatments are not currently available, partly due to lack of animal models that resemble human SUDEP. Recently, it has been reported that two substrains of DBA (DBA/1 and DBA/2) mice exhibit respiratory arrest, leading to cardiac arrest after generalized convulsive seizures, as has been observed in humans. Interestingly, systematic administration of a drug that enhances synaptic serotonin (5-HT) levels significantly reduced respiratory arrest evoked by generalized seizures in DBA mice, suggesting that 5-HT neurotransmission may play an important role in SUDEP. A recent retrospective clinical report indicates that seizure-induced respiratory depression is reduced in patients taking similar 5-HT agents. However, the neuronal network sites at which 5-HT may act to reduce seizure-induced respiratory arrest are currently unknown. We hypothesize that insufficient 5-HT neurotransmission in medullary respiratory center causes respiratory arrest evoked by generalized seizures in DBA/1 mice. This hypothesis is based on the following observations. First, medullary respiratory center has a well-established role in respiration, and 5-HT is a key modulator that regulates respiratory rhythm. Second, medullary brain lesions lead to sudden unexpected death in otherwise healthy humans. Third, deficits of 5-HT neurotransmission in medulla play a causative role in sudden infant death syndrome, a disorder thought to share similar pathophysiology with SUDEP. Finally, it has been shown that several subtypes of 5-HT receptors are abnormal in the brainstem (containing medullary respiratory center) of a substrain of DBA mice. We will test this hypothesis in DBA/1 mice because DBA/1 mice display susceptibility to respiratory arrest for several weeks more than DBA/2 mice (7 days). The specific aims of our proposal are to: 1) determine the effect of enhancing 5-HT neurotransmission in brainstem on respiratory arrest induced by generalized seizures in DBA/1 mice, and 2) determine whether and which 5-HT receptors in the pre-Botzinger complex of medullary respiratory center are involved in seizure-evoked respiratory arrest. Successful implementation of the proposed studies will not only shed important light on the mechanisms of SUDEP but also provide useful information on treatments for this devastating epileptic event. PUBLIC HEALTH RELEVANCE: Sudden unexpected death in epilepsy (SUDEP) is the major cause of death related to epilepsy. The pathophysiology of SUDEP is poorly understood, and there is a lacking in therapeutic and preventive treatments for this disorder. The goal of this research is to elucidate the neural circuit mechanisms of SUDEP to facilitate the development of effective treatment.