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Epilepsy and dendritic excitability

癫痫和树突状兴奋性

基本信息

批准号：
7812548
负责人：
NICHOLAS P POOLOS
金额：
$ 39万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-01-01 至 2010-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7812548
关键词：
Affect Animal Model Anisomycin Antiepileptic Agents Biochemical Biochemical Pathway Biological Assay Brain Brain region Chronic Cyclic Nucleotides Dependence Development Down-Regulation Electroencephalography Electrophysiology (science)Epilepsy Epileptogenesis Frequencies Funding Gated Ion Channel Generalized seizures Generations HCN1 channel Hippocampus (Brain)Ion Channel Link MAP Kinase Gene MAPK14 gene Mediating Membrane Potentials Mitogens Molecular Neocortex Neurons Outcome Outcome Study Pathogenesis Pathway interactions Patients Pharmaceutical Preparations Phosphoric Monoester Hydrolases Phosphorylation Phosphotransferases Pilocarpine Play Population Preparation Process Property Protein Dephosphorylation Regulation Role Seizures Signal Pathway Signal Transduction Slice Status Epilepticus Techniques Temporal Lobe Epilepsy Testing Thalamic structure Up-Regulation abstracting cyclic-nucleotide gated ion channels disability drug development improved in vivo inhibitor/antagonist knockout animal lamotrigine neocortical nervous system disorder neuronal excitability novel prevent research study treatment strategy voltage

项目摘要

Project Summary/Abstract Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels are voltage-gated ion channels that modulate excitability in several brain regions involved in the pathogenesis of epilepsy, including hippocampus, neocortex, and thalamus. The preponderance of evidence shows that downregulation of Ih, the current generated by HCN channels, is associated with neuronal hyperexcitability and epilepsy. In the prior funding period of this project, the onset of epilepsy in an animal model was found to be associated with loss of HCN channel expression, and downregulation of HCN channel gating (i.e. hyperpolarization of Ih voltage-dependent activation). This latter change in HCN channel properties may be particularly important in the generation of seizures, as lamotrigine, an antiepileptic drug, produces upregulation of HCN channel gating as part of its antiepileptic action. A novel modulator of HCN channel gating, p38 mitogen- activated kinase (p38 MAPK), was characterized as well, with inhibition of p38 MAPK causing downregulation of HCN gating. In the present proposal, the links between phosphorylation (i.e. kinase or phosphatase) signalling and HCN channels will be explored. The overall hypothesis is that the downregulation of HCN channel gating that occurs in epilepsy may be due to loss of kinase activity, such as that of p38 MAPK, or to increased phosphatase activity. We will also explore whether direct modulation of p38 MAPK activity exerts an antiepileptic action in vivo. Specifically, we will answer the following questions: 1) Is altered HCN channel gating in epilepsy associated with loss of kinase activity? 2) Is altered HCN channel gating in epilepsy associated with increased phosphatase activity? 3) Is upregulation of HCN gating via activation of p38 MAPK signalling effective in an animal model of temporal lobe epilepsy (TLE)? To answer these questions, we will use cellular electrophysiology techniques in the brain slice preparation, biochemical techniques to assay kinase and phosphatase activity, and long-term video-electroencephalography (VEEG) in the pilocarpine animal model of epilepsy. The outcome of these experiments should increase our understanding of the molecular mechanisms by which seizures alter ion channel biophysical properties, determine whether epilepsy is associated with derangement of phosphorylation signalling pathways, and explore possible novel antiepileptic treatment strategies.

项目总结/摘要超极化激活的环核苷酸门控（HCN）通道是电压门控的离子通道，调节参与神经元兴奋的几个脑区的兴奋性。癫痫的发病机制，包括海马，新皮层和丘脑。的大量证据表明，Ih的下调，由 HCN通道与神经元过度兴奋和癫痫有关。现有在本项目的资助期间，在动物模型中发现癫痫发作是与HCN通道表达的丧失和HCN通道表达的下调相关。门控（即Ih电压依赖性激活的超极化）。后一种变化， HCN通道特性在癫痫发作的产生中可能特别重要，拉莫三嗪是一种抗癫痫药物，它的抗癫痫作用。一种新的HCN通道门控调节剂，p38丝裂原- 活化激酶（p38 MAPK），以及表征，与抑制p38 MAPK 引起HCN门控的下调。在本建议中，磷酸化（即激酶或磷酸酶）将探索信号传导和HCN通道。总的假设是，在癫痫中发生的HCN通道门控的下调可能是由于激酶活性，如p38 MAPK的活性，或增加的磷酸酶活性。我们将我们还将探讨直接调节p38 MAPK活性是否具有抗癫痫作用，体内作用。具体来说，我们将回答以下问题：1）是改变HCN 与激酶活性丧失相关的癫痫通道门控？2)是改变的HCN 癫痫的通道门控与磷酸酶活性增加有关？3)是通过激活p38 MAPK信号传导上调HCN门控在动物中有效颞叶癫痫（TLE）模型？为了回答这些问题，我们将使用蜂窝脑切片制备中的电生理学技术，测定激酶和磷酸酶活性，以及长期视频脑电图在癫痫的匹鲁卡品动物模型中的VEEG。这些实验的结果应该会增加我们对癫痫发作的分子机制的理解，改变离子通道的生物物理特性，确定癫痫是否与磷酸化信号通路的紊乱，并探索可能的新的抗癫痫治疗策略。