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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 该研究的长期目标是了解癫痫病的细胞机制，并找到更好的治疗策略。物质P（SP）是分布在周围和中枢神经系统中的神经肽。体内实验表明SP参与癫痫，但是，这些机制尚不清楚。 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数据），我们建议通过调节海马中间神经元的突触功能来检验SP调节癫痫发生的假设。具体而言，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非级别的非级别的非静态差异分析来确定SP在多大程度上增加AMPAR的开放概率，电导率和/或数字。然后，我们将建立SP受体的三种下游信号通路（磷脂酶C，磷脂酶A2和腺苷酸环化酶）的作用。最后，我们将确定内源释放的SP在增加中间神经元AMPAR功能中的作用。 （2）由于我们的结果表明SP增加了动作电位依赖性GABAA受体介导的自发性IPSC的频率和幅度，因此我们将确定SP兴奋的离子机制，使SP兴奋的神经元增加了GABA释放和SP受体的涉及信号通路； （3）我们将使用毛果皮诱导的海马切片中的癫痫癫痫模型来确定SP是否增加或降低癫痫发作活性，并确定SP受体下游信号传导途径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通过选择性调节中间神经元的SP受体功能来建立一种新的治疗癫痫的方法。