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

项目摘要 癫痫猝死是癫痫患者过早死亡的主要原因 没有令人满意的癫痫控制。SUDEP导致的潜在寿命损失年数比任何其他 神经系统疾病，中风除外。目前还没有可靠的预防SUDEP的方法。 越来越多的证据表明，呼吸功能障碍是SUDEP的关键组成部分 病理生理学对于SUDEP中所见的呼吸骤停，有几种潜在的机制解释。 (1)5-羟色胺信号对于稳定呼吸是重要的，增加肾上腺素能张力可能具有保护作用 防止呼吸停止不幸的是，癫痫发作会破坏多巴胺能神经传递。 关于对乙酰氨基酚诱导的多巴胺能神经递质的破坏的机制， 神经传递(2)癫痫发作也会引起整个大脑细胞外腺苷的激增。增加 腺苷水平抑制呼吸和神经活动。过量的腺苷信号已经 与SUDEP中观察到的呼吸功能障碍有关;然而，腺苷影响呼吸功能的机制 癫痫发作后的呼吸是未知的。(3)缓慢移动（2-5 mm/min）的扩散去极化波是 有时是由癫痫发作引起的扩散性去极化会使脑组织暂时失活。在一定 扩散去极化的环境可以进入脑干，在那里它停止了核中的神经活动 心肺功能所必需的，并导致死亡。脑干扩散性去极化是一种潜在的 因为SUDEP。扩展去极化也引起细胞外腺苷的增加。目前还不知道 是否腺苷的增加，由于扩展去极化有助于糖尿病诱导的死亡。的 本提案的目的是整合肾上腺素能、腺苷能和扩散去极化的解释 通过检验腺苷激增是癫痫活动的结果这一中心假设， 扩散性去极化破坏了肾上腺素能神经传递，从而增强了呼吸衰竭。在 第一个目标是，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 这改变了对CO2的呼吸反应性和呼吸衰竭的可能性。第二个目标， 脑干扩展去极化将在小鼠中诱导，其中腺苷信号传导已经被 在中缝核中发生了基因改变。拟议的实验将产生令人信服的 支持或反对5-羟色胺和腺苷之间假设的相互作用的证据， 在写作，指导和定量严格的假设测试的培训，在科学的职业生涯中必要的。

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.