Role of HCN channels in epilepsy

HCN 通道在癫痫中的作用

基本信息

批准号：
7230221
负责人：
Dane M Chetkovich
金额：
$ 16.22万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-03-01 至 2008-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7230221
关键词：
Absence Epilepsy Address Affect Animal Model Animals Appearance Behavior Behavioral Biochemical Biological Brain C-terminal Calcium Categories Cells Condition Convulsants Cyclic Nucleotides Defect Dendrites Development Diagnostic tests Distal Electroencephalography Electromyography Elements Epilepsy Exhibits Exons Febrile Convulsions Functional disorder Gated Ion Channel Genes Genetic Goals Heart Hippocampus (Brain)Human In Situ Hybridization Individual Integral Membrane Protein Ion Channel Knock-out Knockout Mice Ligands Localized Mediating Membrane Membrane Potentials Messenger RNA Molecular Monitor Mus Mutant Strains Mice Mutation Myoclonic Epilepsies Names Neurons Northern Blotting Nucleotides Patients Pharmaceutical Preparations Phenotype Play Population Predisposition Proteins Recurrence Research Personnel Role Scaffolding Protein Seizures Signal Transduction Site Surface Synapses Syndrome Tail Techniques Testing Thalamic structure Western Blotting brain cell cyclic-nucleotide gated ion channels hippocampal pyramidal neuron insight mouse model mutant neuronal cell body neuronal excitability novel novel diagnostics positional cloning programs protein protein interaction spelling trafficking voltage

项目摘要

DESCRIPTION (provided by applicant): Epilepsy, the condition in which affected individuals suffer recurrent seizures, affects up to 2% of the population. Many familial epilepsy syndromes have been characterized, pointing to genetic factors that may predispose toward or underlie many cases of epilepsy. In addition to genetic approaches to identifying genes involved in human epilepsy syndromes, mouse models of epilepsy have further illuminated the important role of ion channels in epilepsy, and have demonstrated overlap between human and mouse epilepsy genes. One category of voltage-gated ion channels implicated in epilepsy is the hyperpolarization-activated cyclic nucleotide-gated (HCN) ion channel, which underlies the hyperpolarization-activated current (In). HCN channels mediate rhythmic oscillations in neuronal membrane potential and play an important role in membrane excitability and dendritic signal integration. A spontaneous mutant mouse with a 4-nucleotide insertion in the C-terminus of the hyperpolarization-activated cyclic nucleotide-gated channel subunit 2 (HCN2) gene has recently been identified. This mutant, named apathetic, is ataxic, and exhibits brief behavioral arrest spells consistent with absence seizures and paroxysmal jumping behavior followed by post-ictal immobility that is consistent with myoclonic seizures. The apathetic mutation is predicted to produce a protein with a truncation of a large portion of the C-terminal tail of HCN2. Protein-protein interactions between ion channel C-termini and scaffolding proteins often regulate ion channel localization, and abnormalities of HCN channel subcellular distribution may play a role in epilepsy. This proposal will utilize EEG recording, behavioral monitoring, cell biological and biochemical techniques to test the hypothesis that truncation of the HCN2 C-terminus in apathetic mice causes epilepsy by mislocalization of HCN channels in thalamic neurons, as well as in cortical and hippocampal pyramidal neurons, resulting in abnormal excitability and epilepsy. The immediate aims of this proposal are to characterize a novel animal model of spontaneous genetic epilepsy and to add insight into the basic molecular mechanisms that underlie some forms of epilepsy, with the ultimate goal of identifying targets for new diagnostic testing and treatments for epilepsy.

描述（由申请人提供）：癫痫病，即受影响个体经常性癫痫发作的状况，影响多达2％的人口。许多家族性癫痫综合症已经表征了，这表明遗传因素可能倾向于或基于许多癫痫病例。除了鉴定与人癫痫综合症有关的基因的遗传方法外，癫痫的小鼠模型还进一步阐明了离子通道在癫痫中的重要作用，并且已经证明了人类和小鼠癫痫基因之间的重叠。与癫痫有关的一类电压门控离子通道是超极化循环核苷酸门控（HCN）离子通道，该通道是高极化激活的电流的基础（IN）。 HCN通道介导神经元膜电位中的节奏振荡，并在膜兴奋性和树突状信号整合中起重要作用。最近已经鉴定出了超极化激活循环核苷酸门控通道亚基2（HCN2）基因的自发性突变小鼠在C末端中插入4-核苷酸。这个称为无动于衷的突变体是共同的，并且表现出与缺席和阵发性跳跃行为一致的简短行为停滞法术，然后出现与肌阵挛性癫痫发作一致的造成后固定性。预测冷静的突变会产生一种蛋白质，其截断是HCN2的C末端尾部的大部分。离子通道C末端与支架蛋白之间的蛋白质 - 蛋白质相互作用通常调节离子通道定位，而HCN通道亚细胞分布的异常可能在癫痫中起作用。 This proposal will utilize EEG recording, behavioral monitoring, cell biological and biochemical techniques to test the hypothesis that truncation of the HCN2 C-terminus in apathetic mice causes epilepsy by mislocalization of HCN channels in thalamic neurons, as well as in cortical and hippocampal pyramidal neurons, resulting in abnormal excitability and癫痫。该提案的直接目的是表征一种自发遗传癫痫的新型动物模型，并洞悉基本的分子机制，这些机制是某种形式的癫痫病，其最终目标是确定对新诊断测试和癫痫治疗的靶标。