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

中枢 5-HT 传输在癫痫发作引起的呼吸骤停中的作用

• 批准号: 8283020
• 负责人: Huajun Feng
• 金额: $ 8.11万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8283020
• 关键词: Animal Model; Backcrossings; Brain; Brain Stem; Cause of Death; Cessation of life; Clinical; Complex; Complication; DBA/1 Mouse; DBA/2 Mouse; Development; Disease; Epilepsy; Event; Exhibits; Functional disorder; Generalized seizures; Generations; Goals; Heart Arrest; Human; Inbred DBA Mice; Lead; Lesion; Light; Microinjections; Motor Seizures; Mus; Neurons; Patients; Pharmaceutical Preparations; Play; Predisposition; Preventive; Reducing Agents; Reporting; Research; Respiration; Respiratory Center; Risk Factors; Rodent; Role; Seizures; Selective Serotonin Reuptake Inhibitor; Serotonin; Site; Structure; Study models; Sudden Death; Sudden infant death syndrome; Synapses; TDO2 gene; Testing; Therapeutic; Time; Transgenic Organisms; Ventilatory Depression; base; cardiac depression; effective therapy; inhibitor/antagonist; neural circuit; neurotransmission; prevent; receptor; respiratory; reuptake; transmission process

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.

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毁灭性癫痫并发症。癫痫引起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于人类SUDEP的动物模型。最近，据报道，DBA的两个亚系（DBA/1和DBA/2）小鼠表现出呼吸停止，导致全身性惊厥发作后心脏骤停，如已在人类中观察到的。有趣的是，系统给药的药物，提高突触5-羟色胺（5-HT）水平显着减少呼吸骤停诱发的全身性癫痫发作DBA小鼠，这表明5-HT神经传递可能在SUDEP中发挥重要作用。最近的一项回顾性临床报告表明，在服用类似5-HT药物的患者中，麻醉诱导的呼吸抑制减少。然而，神经网络网站5-HT可能会采取行动，以减少麻醉诱导的呼吸骤停是目前未知的。我们推测，在DBA/1小鼠中，延髓呼吸中枢的5-HT神经传递不足引起全身性癫痫发作引起的呼吸骤停。这一假设基于以下观察。首先，延髓呼吸中枢在呼吸活动中的作用已得到证实，而5-HT是调节呼吸节律的关键调节剂。第二，脑髓质病变导致原本健康的人意外猝死。第三，髓质5-HT神经传递的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有着相似的病理生理学。最后，它已被证明，5-羟色胺受体的几个亚型是异常的脑干（含延髓呼吸中心）的DBA小鼠亚系。我们将在DBA/1小鼠中检验这一假设，因为DBA/1小鼠比DBA/2小鼠（7天）更易发生呼吸骤停数周。我们的具体目标是：1）确定增强脑干5-HT神经传递对DBA/1小鼠全身性癫痫发作引起的呼吸停止的影响; 2）确定延髓呼吸中枢前Botzinger复合体中的5-HT受体是否以及哪些参与了癫痫引起的呼吸停止。这些研究的成功实施不仅将为SUDEP的机制提供重要的启示，而且还将为这种毁灭性癫痫事件的治疗提供有用的信息。 癫痫猝死（SUDEP）是癫痫相关死亡的主要原因。SUDEP的病理生理学知之甚少，并且缺乏对这种疾病的治疗和预防性治疗。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。