Substance P in the Central Respiratory Neural Network

描述（由申请人提供）：过度换气、屏气、中枢呼吸暂停和呼吸节律障碍是Rett综合征患者的典型症状。在这些患者中，P物质在与呼吸中枢控制有关的脑干区域缺乏。因此，我们假设RS的不规则呼吸是由于脑干缺乏P物质（“P物质假说”）。我们还假设，了解P物质（SP）如何控制呼吸对于开发RS呼吸障碍的合理疗法至关重要。拟议的资助申请旨在研究P物质在调节中枢神经控制呼吸方面的作用，将在小鼠横切脑干切片中分离呼吸网络的关键部分（“前波青格复合物”）。提出的研究解决了3个基本问题：(1)哪种类型的离子通道被SP调制？具体目的1检验SP调节呼吸神经元低阈值钠电流的假设。假设的离子通道在吸气非起搏器和起搏器神经元中引起持久的去极化，导致呼吸网络的兴奋反应。(2) SP如何改变呼吸起搏器神经元的膜性质？具体目标2测试了低阈值钠电流与负责产生起搏器活动的离子通道相互作用的假设。我们特别研究了这种钠通道是否会导致CAN电流的激活，CAN电流会显著增强镉敏感起搏器神经元的破裂。这一目标将导致更好地理解负责SP调制的机制以及呼吸起搏器神经元中爆发产生的离子机制。(3)起搏器神经元是否依赖于SP的内源性激活？特异性目的3验证了内源性释放SP是通过调节起搏器神经元来维持正常呼吸活动的假设。SP水平降低会导致起搏器活动减弱，从而导致呼吸不规则。这项研究计划的预期结果将为RS提供重要的相关概念，因为它将更好地理解为什么低水平的SP会导致不规则的呼吸活动。

DESCRIPTION (provided by applicant): Hyperventilation, breath-holding, central apnea and respiratory dysrhythmia is typical for patients with Rett Syndrome. In these patients, substance P is deficient in brainstem areas that are associated with the central control of breathing. Therefore we hypothesize that the irregular breathing in RS is due to the brainstem deficiency in Substance P ("Substance P hypothesis"). We also hypothesize that an understanding of how substance P (SP) controls breathing will be essential for developing rational therapies for the breathing disorders in RS. The proposed grant application, aimed at investigating the role of substance P in regulating the central nervous control of breathing, will isolate a critical portion of the respiratory network (the "pre- Botzinger complex") in a transverse brainstem slice from mice. The proposed research addresses 3 fundamental questions: (1) What type of ion channel is modulated by SP? Specific aim 1 examines the hypothesis that SP modulates a low-threshold sodium current in respiratory neurons. The hypothesized ion channel causes a long lasting depolarization in inspiratory non-pacemaker and pacemaker neurons resulting in an excitatory response of the respiratory network. (2) How does SP alter membrane properties of respiratory pacemaker neurons? Specific aim 2 tests the hypothesis that the low-threshold sodium current interacts with the ion channels responsible for the generation of pacemaker activity. We specifically examine whether this sodium channel leads to the activation of a CAN current, which dramatically enhances bursting in cadmium-sensitive pacemaker neurons. This aim will lead to a better understanding of the mechanisms responsible for the SP modulation as well as the ionic mechanisms underlying burst generation in respiratory pacemaker neurons. (3) Are pacemaker neurons dependent on the endogenous activation by SP? Specific aim 3 tests the hypothesis that endogenously released SP is required to maintain regular respiratory activity by modulating pacemaker neurons. Decreased levels of SP will lead to weakening of pacemaker activity and thus to irregular breathing. The expected outcome of this research plan will provide important concepts relevant for RS as it will lead to a better understanding of why low levels of SP cause irregular respiratory activity.