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

项目摘要 癫痫患者猝死是导致癫痫患者过早死亡的主要原因。 他们没有令人满意的癫痫控制。SUDEP导致的潜在寿命损失年数比其他任何项目都要多 除中风外的神经系统疾病。目前还没有已知的可靠预防SUDEP的方法。 一致的证据表明，呼吸功能障碍是SUDEP的关键组成部分 病理生理学。对于SUDEP中出现的呼吸骤停，有几种潜在的机械解释。 (1)5-羟色胺信号对稳定呼吸很重要，增加5-羟色胺能张力可能具有保护作用 对抗癫痫引起的呼吸骤停。不幸的是，癫痫发作会扰乱5-羟色胺能神经传递。 关于癫痫引起的5-羟色胺能神经元紊乱的机制，人们知之甚少。 神经传递。(2)癫痫发作还会导致整个大脑中细胞外腺苷的激增。增加 腺苷水平抑制呼吸，抑制神经活动。过量的腺苷信号一直是 与SUDEP的呼吸功能障碍有关；然而，腺苷影响的机制 癫痫发作后的呼吸是未知的。(3)缓慢移动(2-5 mm/min)的扩散型去极化波 有时是由癫痫发作引发的。散布的去极化会暂时使脑组织失活。在某些情况下 传播去极化的环境可以进入脑干，在那里它停止核团中的神经活动。 对心肺功能是必需的，并会导致死亡。脑干扩散去极化是一种潜在的 SUDEP的起因。扩散性去极化也会导致细胞外腺苷的增加。目前尚不清楚 扩散性去极化引起的腺苷增加是否会导致癫痫发作导致的死亡。这个 这项建议的目标是整合5-羟色胺能、腺苷能和广泛性去极化的解释 通过检验腺苷激增是癫痫活动和癫痫发作的结果的中心假说 扩散的去极化扰乱了5-羟色胺能神经传递，从而加重了呼吸衰竭。在 第一个目标是，在癫痫发作期间，5-羟色胺能中缝核中的腺苷信号将被增强，以确定是否 这改变了呼吸对二氧化碳的反应性和呼吸衰竭的可能性。在第二个目标中， 在腺苷信号已被激活的小鼠中，脑干扩散性去极化将被诱导 在中缝核团中发生药理或基因改变。拟议的实验将产生令人信服的 证据支持或反对5-羟色胺和腺苷之间的假设相互作用，同时提供 在写作、指导和严格的数量假设检验方面的培训，这是从事科学工作所必需的。

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.