Substance P in the Central Respiratory Neural Network

描述(申请人提供)：过度换气、屏气、中枢性呼吸暂停和呼吸节律失常是Rett综合征患者的典型症状。在这些患者中，与呼吸中枢控制相关的脑干区域中P物质缺乏。因此，我们假设RS患者的不规则呼吸是由于脑干中P物质缺乏所致(“P物质假说”)。我们还假设，对P物质(SP)如何控制呼吸的了解将是开发RS呼吸障碍的合理治疗方法的关键。拟议的拨款申请旨在研究P物质在调节呼吸的中枢神经控制中的作用，将从小鼠的横向脑干切片中分离出呼吸网络的一个关键部分(“波辛格前复合体”)。这项研究涉及三个基本问题：(1)SP调节的是哪种类型的离子通道？特定目的1检验SP调节呼吸神经元低阈值钠电流的假说。假想的离子通道在吸气性非起搏器和起搏器神经元中引起持久的去极化，从而导致呼吸网络的兴奋性反应。(2)SP如何改变呼吸起搏神经元膜的特性？特定目标2测试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导致CaN电流的激活，从而显著增强了镉敏感的起搏器神经元的爆发。这一目标将有助于更好地理解SP调制的机制以及呼吸起搏神经元产生猝发的离子机制。(3)起搏神经元是否依赖于SP的内源性兴奋？特殊目的3验证了这样的假设，即内源性释放的SP需要通过调节起搏神经元来维持正常的呼吸活动。SP水平降低会导致起搏器活动减弱，从而导致呼吸不规律。这项研究计划的预期结果将提供与RS相关的重要概念，因为它将有助于更好地理解为什么低水平的SP会导致呼吸活动不规律。

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.