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

描述（由申请人提供）：癫痫猝死（SUDEP）是一种与全身性癫痫发作相关的破坏性癫痫并发症。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的两个亚株（DBA/1和DBA/2）小鼠表现出呼吸骤停，导致全身惊厥发作后心脏骤停，正如在人类中观察到的那样。有趣的是，系统给药可提高突触5-羟色胺（5-HT）水平的药物可显著降低DBA小鼠全身癫痫发作引起的呼吸骤停，这表明5-HT神经传递可能在SUDEP中起重要作用。最近的一项回顾性临床报告表明，服用类似5-HT药物的患者癫痫引起的呼吸抑制减少。然而，目前尚不清楚5-HT可能在哪些神经元网络位点起作用，以减少癫痫引起的呼吸骤停。我们假设在DBA/1小鼠中，髓质呼吸中枢的5-HT神经传递不足导致了全局性癫痫发作引起的呼吸骤停。这一假设是基于以下观察。首先，髓质呼吸中枢在呼吸中的作用已经确立，而5-HT是调节呼吸节律的关键调节剂。其次，脑髓质病变会导致原本健康的人突然意外死亡。第三，髓质5-HT神经传递缺陷在婴儿猝死综合征中起着致病作用，这种疾病被认为与SUDEP具有相似的病理生理学。最后，研究表明，在DBA小鼠亚系的脑干（包括髓质呼吸中枢）中，有几种亚型的5-HT受体异常。我们将在DBA/1小鼠中验证这一假设，因为DBA/1小鼠比DBA/2小鼠（7天）更容易出现呼吸骤停数周。本研究的具体目的是：1)确定增强脑干5-HT神经传递对DBA/1小鼠全发性癫痫引起的呼吸骤停的影响；2)确定髓质呼吸中枢前波青格复合物中5-HT受体是否以及哪些受体参与癫痫引起的呼吸骤停。成功实施拟议的研究不仅将对SUDEP的机制提供重要的启示，而且还将为这一破坏性癫痫事件的治疗提供有用的信息。

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.