COBRE: UND: CELLULAR MECHANISMS OF SUBSTANCE P IN EPILEPSY

COBRE：UND：P 物质在癫痫中的细胞机制

• 批准号: 7610476
• 负责人: Saobo Lei
• 金额: $ 17.06万
• 依托单位: UNIVERSITY OF NORTH DAKOTA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-07 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7610476
• 关键词: AMPA Receptors; Action Potentials; Address; Adenylate Cyclase; Analysis of Variance; Chromosome Pairing; Computer Retrieval of Information on Scientific Projects Database; Data; Epilepsy; Epileptogenesis; Frequencies; Funding; Goals; Grant; Hippocampus (Brain); Institution; Interneurons; Mediating; Modeling; Neuraxis; Neuropeptides; Numbers; Peripheral; Phospholipase A2; Phospholipase C Signaling Pathway; Pilocarpine; Play; Postsynaptic Membrane; Probability; Research; Research Personnel; Resources; Role; Seizures; Signal Pathway; Slice; Source; Substance P; Substance P Receptor; Synapses; Synaptic Transmission; Testing; United States National Institutes of Health; alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid; amino 3 hydroxy 5 methylisoxazole 4 propionate; base; gamma-Aminobutyric Acid; in vivo; novel strategies; postsynaptic; receptor; receptor function; research study; selective expression; synaptic function

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The long-term goal of the research is to understand the cellular mechanisms underlying epilepsy and to find a better strategy for its treatment. Substance P (SP) is a neuropeptide distributed in both the peripheral and central nervous systems. In vivo experiments show that SP is involved in epilepsy, however, the mechanisms are unknown. Based on the observations that 1) the GABAergic interneurons in hippocampus play a pivotal role in epilepsy, 2) SP receptors are selectively expressed by interneurons and 3) SP enhances both AMPA receptor (AMPAR)-mediated excitatory and GABAA-receptor-mediated inhibitory synaptic transmissions onto interneurons in hippocampal slices (our preliminary data), we propose to test a hypothesis that SP modulates epileptogenesis by regulating the synaptic functions of hippocampal interneurons. Specifically, we intend to address the following issues: (1) Because SP increases AMPA EPSCs by a postsynaptic mechanism, we will determine the extent to which SP increases AMPAR open probability, conductance and/or numbers on postsynaptic membranes at hippocampal interneuron synapses by using peak-scaled non-stationary variance analysis. We will then establish the roles of three downstream signaling pathways (phospholipase C, phospholipase A2 and adenylyl cyclase) of SP receptors in the effects of SP. Finally, we will determine the roles of endogenously released SP in increasing interneuron AMPAR function; (2) Because our results show that SP increases both the frequency and the amplitude of action potential-dependent GABAA receptor-mediated spontaneous IPSCs at interneuron synapses, we will determine the ionic mechanisms by which SP excites interneurons to increase GABA release and the involved signaling pathways of SP receptors; (3) We will determine whether SP increases or decreases seizure activity using a pilocarpine-induced epilepsy model in hippocampal slices and determine the roles of the signaling pathways downstream of SP receptors in seizures. Because SP receptors are exclusively distributed on hippocampal interneurons, our research may help establish a novel approach for treating epilepsy by selectively modulating SP receptor functions on interneurons.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 该研究的长期目标是了解癫痫的细胞机制并找到更好的治疗策略。 P物质（SP）是一种分布在外周和中枢神经系统中的神经肽。体内实验表明SP与癫痫有关，但其机制尚不清楚。基于以下观察：1) 海马中的 GABA 能中间神经元在癫痫中发挥关键作用，2) SP 受体由中间神经元选择性表达，3) SP 增强 AMPA 受体 (AMPAR) 介导的兴奋性和 GABAA 受体介导的抑制性突触传输到海马切片中的中间神经元（我们的初步数据），我们建议检验 SP 通过调节癫痫发生的假设海马中间神经元的突触功能。具体来说，我们打算解决以下问题：（1）由于 SP 通过突触后机制增加 AMPA EPSC，因此我们将通过使用峰值尺度非平稳方差分析。然后我们将确定 SP 受体的三个下游信号通路（磷脂酶 C、磷脂酶 A2 和腺苷酸环化酶）在 SP 作用中的作用。最后，我们将确定内源性释放的 SP 在增强中间神经元 AMPAR 功能中的作用； (2) 因为我们的结果表明 SP 增加了中间神经元突触处动作电位依赖性 GABAA 受体介导的自发 IPSC 的频率和幅度，所以我们将确定 SP 兴奋中间神经元以增加 GABA 释放的离子机制以及相关的信号传导SP受体途径； (3)我们将使用海马切片中毛果芸香碱诱导的癫痫模型确定SP是否增加或减少癫痫发作活动，并确定SP受体下游信号通路在癫痫发作中的作用。由于SP受体专门分布在海马中间神经元上，因此我们的研究可能有助于建立一种通过选择性调节中间神经元上SP受体功能来治疗癫痫的新方法。