Mechanisms of regulation of excitability in immature CNS

未成熟中枢神经系统兴奋性的调节机制

• 批准号: 7405620
• 负责人: JOAQUIN N LUGO
• 金额: $ 5.13万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-12-06 至 2010-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7405620
• 关键词: Action Potentials; Acute; Adult; Age; Americas; Animal Model; Animals; Back; Behavioral; Brain; Child; Childhood; Convulsants; Data; Dendrites; Development; Diagnosis; Down-Regulation; Epilepsy; Glutamate Receptor; Goals; Heterozygote; Hippocampus (Brain); Human; Immunofluorescence Immunologic; Investigation; Kainic Acid; Knock-out; Knockout Mice; Kv4.2 channel; Learning; Life; Localized; Long-Term Effects; Membrane; Molecular Biology Techniques; Molecular Profiling; Monitor; Morbidity - disease rate; Mus; Neurons; Neurotransmitters; Numbers; Pediatric Hospitals; Pediatric Intensive Care Units; Pilot Projects; Play; Potassium; Potassium Channel; Predisposition; Pyramidal Cells; Rate; Recording of previous events; Regulation; Risk Factors; Rodent; Role; Seizures; Status Epilepticus; Synapses; System; Testing; Thinking; Time; Weight; Western Blotting; behavior test; day; early experience; early onset; gamma-Aminobutyric Acid; insight; mortality; mossy fiber; novel; postnatal; postsynaptic; therapeutic target; tool; voltage

DESCRIPTION (provided by applicant): Prolonged, continuous seizure activity (status epilepticus) is associated with significant mortality and morbidity, particularly in children. In humans and animal models of epilepsy the immature brain is highly susceptible to seizures. The neurotransmitter systems in the developing brain are weighted toward excitation and the inhibitory systems present in developing brain to dampen excitation are not well characterized. In adult brain potassium channels are major determinants of membrane excitability in neurons. One particular potassium channel, Kv4.2 is localized to the dendrites of hippocampal neurons where they form the transient A-type K+ current. In this region where the neurons receive synaptic input, the voltage-dependent activation of Kv4.2 channels provides a critical mechanism for regulating postsynaptic excitability. A number of voltage-dependent potassium channels are not expressed early in developing brain; however our pilot studies show that Kv4.2 channels are expressed at adult levels in immature brain. Thus, we hypothesize that the potassium channel Kv4.2 is expressed early in development and may be critical for dampening excitability in the immature brain. We propose the following aims: Aim 1: Investigation of the role of Kv4.2 channels in the regulation of excitability in the immature brain. We will evaluate expression levels and localization of Kv4.2 channel subunits in immature compared with adult mice. To assess the role of Kv4.2 channels in seizure susceptibility in immature brain we will perform convulsant stimulation in Kv4.2 knockout compared with heterozygote and wildtype mice. Aim 2: Investigation of the role of Kv4.2 channels in the development of long-term changes after early-life seizures. We will evaluate whether early-life status epilepticus leads to more profound long-term alterations in Kv4.2 knockout compared to wildtype and heterozygous mice. Long-term parameters that we will monitor are development of spontaneous seizures, neuroanatomical changes in hippocampus, and spatial learning deficits. The overall goal of this proposal to elucidate candidate mechanisms involved in regulating excitability and seizure susceptibility in immature brain and the long-term consequences of early-life status epilepticus. Relevance: Status epilepticus (uncontrollable continuous seizures) is one of the most common diagnoses for children transported to the Pediatric Intensive Care Units at a number of major children's hospitals and is associated with serious long-term consequences. Our studies are anticipated to provide insights into the mechanisms involved in regulating seizure susceptibility and status epilepticus in the developing brain and thereby may identify novel candidate targets for therapeutics in childhood epilepsy.

描述（由申请人提供）：长期持续的癫痫发作活动（癫痫持续状态）与显著的死亡率和发病率相关，尤其是在儿童中。在人类和癫痫动物模型中，未成熟的大脑对癫痫发作高度敏感。发育中的大脑中的神经递质系统倾向于兴奋，而发育中的大脑中存在的抑制兴奋的抑制系统还没有得到很好的表征。在成人脑中，钾通道是神经元膜兴奋性的主要决定因素。一种特殊的钾通道Kv4.2定位于海马神经元的树突，在那里它们形成瞬时A型K+电流。在神经元接受突触输入的这个区域中，Kv4.2通道的电压依赖性激活提供了调节突触后兴奋性的关键机制。许多电压依赖性钾通道在发育中的大脑中早期不表达;然而，我们的初步研究表明，Kv4.2通道在未成熟大脑中以成人水平表达。因此，我们假设钾通道Kv4.2在发育早期表达，可能对抑制未成熟大脑的兴奋性至关重要。我们提出以下目的：目的1：研究Kv4.2通道在未成熟脑兴奋性调节中的作用。我们将评估Kv4.2通道亚基在未成熟小鼠和成年小鼠中的表达水平和定位。为了评估Kv4.2通道在未成熟脑中癫痫易感性中的作用，我们将在Kv4.2敲除小鼠中与杂合子和野生型小鼠相比进行惊厥刺激。目的2：研究Kv4.2通道在早期癫痫发作后长期变化发展中的作用。我们将评估与野生型和杂合子小鼠相比，早期癫痫持续状态是否会导致Kv4.2敲除小鼠更深刻的长期改变。我们将监测的长期参数是自发性癫痫发作、海马神经解剖学变化和空间学习缺陷的发展。这项提案的总体目标是阐明参与调节未成熟大脑兴奋性和癫痫易感性的候选机制以及早期癫痫持续状态的长期后果。相关性：癫痫持续状态（无法控制的持续癫痫发作）是许多大型儿童医院儿科重症监护室最常见的儿童诊断之一，并与严重的长期后果有关。我们的研究有望为发育中大脑中调节癫痫发作易感性和癫痫持续状态的机制提供见解，从而可能确定儿童癫痫治疗的新候选靶点。