Role of adenosinergic inhibition of serotonin neurons in seizure induced respiratory arrest

腺苷能抑制血清素神经元在癫痫发作引起的呼吸骤停中的作用

• 批准号: 10599873
• 负责人: Benton Scott Purnell
• 金额: $ 6.87万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-23 至 2025-05-22
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599873
• 关键词: Adenosine; Affect; Arousal; Brain; Brain Stem; Breathing; Carbon Dioxide; Cause of Death; Cell Nucleus; Cessation of life; Disease; Epilepsy; Etiology; Functional disorder; Goals; Knowledge; Life; Link; Mentorship; Mus; Neural Inhibition; Neurologic; Neurons; Patients; Persons; Prevention; Regulation; Respiration Disorders; Respiratory Failure; Respiratory physiology; Role; Science; Seizures; Serotonergic System; Serotonin; Signal Transduction; Stroke; System; Testing; Therapeutic; Tissues; Training; Travel; Writing; brain tissue; career; epileptiform; expectation; experimental study; extracellular; insight; neural; neurotransmission; pharmacologic; premature; prevent; raphe nuclei; respiratory; sudden unexpected death in epilepsy

Project Summary Sudden unexpected death in epilepsy (SUDEP) is the leading cause of premature death in persons with epilepsy who do not have satisfactory seizure control. SUDEP results in more years of potential life lost than any other neurological condition with the exception of stroke. There are no known ways of reliably preventing SUDEP. Convergent lines of evidence suggest that respiratory dysfunction is a critical component of SUDEP pathophysiology. There are several potential mechanistic explanations for the respiratory arrest seen in SUDEP. (1) Serotonin signaling is important for stable breathing and increasing serotonergic tone may be protective against seizure-induced respiratory arrest. Unfortunately, seizures disrupt serotonergic neurotransmission. There is a gap in knowledge as to the mechanism responsible for seizure-induced disruption of serotonergic neurotransmission. (2) Seizures also cause a surge in extracellular adenosine throughout the brain. Increases in adenosine levels suppress breathing and inhibit neural activity. Excessive adenosine signaling has been implicated in the respiratory dysfunction seen in SUDEP; however, the mechanism by which adenosine affects breathing after seizures is unknown. (3) Slow moving (2-5 mm/min) waves of spreading depolarization are sometimes triggered by seizures. Spreading depolarization transiently inactivates the brain tissue. Under certain circumstances spreading depolarization can travel into the brainstem where it halts neural activity in nuclei necessary for cardiorespiratory function and causes death. Brainstem spreading depolarization is a potential cause of SUDEP. Spreading depolarization also causes an increase in extracellular adenosine. It is not known whether the increase in adenosine due to spreading depolarization contributes to seizure-induced death. The goal of this proposal is to integrate the serotonergic, adenosinergic, and spreading depolarization explanations of SUDEP etiology by testing the central hypothesis that adenosine surging as the result of seizure activity and spreading depolarization disrupts serotonergic neurotransmission thereby potentiating respiratory failure. In the first aim, adenosine signaling will be augmented in the serotonergic raphe nuclei during seizures to determine if this alters respiratory responsiveness to CO2 and the likelihood of respiratory failure. In the second aim, brainstem spreading depolarization will be induced in mice in which adenosine signaling has been pharmacologically or genetically altered in the raphe nuclei. The proposed experiments will generate compelling evidence for or against the hypothesized interaction between serotonin and adenosine while providing the training in writing, mentorship, and quantitatively rigorous hypothesis-testing necessary for a career in science.

项目概要 癫痫猝死（SUDEP）是癫痫患者过早死亡的主要原因 癫痫发作控制效果不佳的人。 SUDEP 比其他任何方法都会导致更多年的潜在寿命损失 神经系统疾病（中风除外）。没有已知的方法可以可靠地预防 SUDEP。 多种证据表明呼吸功能障碍是 SUDEP 的一个关键组成部分 病理生理学。对于 SUDEP 中出现的呼吸停止有几种潜在的机制解释。 (1) 血清素信号对于稳定呼吸很重要，增加血清素可能具有保护作用 防止癫痫发作引起的呼吸停止。不幸的是，癫痫发作会破坏血清素能神经传递。 关于癫痫引起的血清素能破坏的机制尚存在知识空白。 神经传递。 (2) 癫痫发作还会导致整个大脑的细胞外腺苷激增。增加 腺苷水平抑制呼吸并抑制神经活动。腺苷信号传导过多 与 SUDEP 中出现的呼吸功能障碍有关；然而，腺苷影响的机制 癫痫发作后的呼吸情况不明。 (3) 传播去极化的慢速移动（2-5 mm/min）波为 有时由癫痫发作引起。去极化的扩散会暂时使脑组织失活。在一定的情况下 传播去极化的环境可以进入脑干，从而阻止细胞核中的神经活动 是心肺功能所必需的并导致死亡。脑干扩散去极化是一种潜在的 SUDEP 的原因。去极化的扩散也会导致细胞外腺苷的增加。目前尚不清楚 由于去极化扩散而导致的腺苷增加是否会导致癫痫引起的死亡。这 该提案的目标是整合血清素能、腺苷能和扩散去极化的解释 通过测试腺苷激增是癫痫发作活动和结果的中心假设来研究 SUDEP 病因学 去极化的扩散会破坏血清素能神经传递，从而加剧呼吸衰竭。在 第一个目标是，在癫痫发作期间，血清素能中缝核中的腺苷信号传导将增强，以确定是否 这会改变呼吸对二氧化碳的反应以及呼吸衰竭的可能性。在第二个目标中， 在腺苷信号传导已被抑制的小鼠中，将诱导脑干扩散去极化。 中缝核中的药理学或遗传改变。拟议的实验将产生引人注目的结果 支持或反对假设的血清素和腺苷之间相互作用的证据，同时提供 科学职业所需的写作、指导和定量严格假设检验方面的培训。