Mechanisms compromising GABAergic synaptic transmission during status epiletpicus

癫痫持续状态期间损害 GABA 能突触传递的机制

基本信息

批准号：
8514739
负责人：
Howard P Goodkin
金额：
$ 31.86万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8514739
关键词：
Action Potentials Adult Age Agreement Animals Benzodiazepines Biochemical Brain Calcium Cells Cessation of life Child Childhood Consensus Development Failure Fire - disasters Frequencies Functional disorder General Population Goals Hippocampus (Brain)Human Incidence Interneurons Laboratory Study Mediating Methods Modification Morbidity - disease rate Myoepithelial cell Nature Neurologic Neurologic Dysfunctions Neurological emergencies Neurons Pathogenesis Pharmaceutical Preparations Population Presynaptic Terminals Process Property Rattus Research Resistance Role Seizures Sprague-Dawley Rats Staging Status Epilepticus Surface Synapses Synaptic Transmission System Techniques Testing Time age related base common treatment design early childhood gamma-Aminobutyric Acid hippocampal pyramidal neuron improved juvenile animal meetings mortality neurodevelopment novel outcome forecast postnatal postsynaptic presynaptic public health relevance quantum receptor research study response trafficking

项目摘要

DESCRIPTION (provided by applicant): Status epilepticus is characterized by a prolonged, self-sustained seizure that can be resistant to current first line therapies. Although it can occur at any age, status epilepticus is the most common neurological emergency of childhood, especially between the ages of 1 month and 4 years. Fortunately, for some children, status epilepticus occurs without consequence. For others, it is associated with death or long term neurological dysfunction. Because the prognosis is dependent on duration, improved therapies for the treatment of status epilepticus are required. Despite agreement that modifications in GABA-mediated synaptic transmission contribute to the pathogenesis of status epilepticus, our understanding of the cellular mechanisms that underlie this process is not complete; and, many of the prior laboratory studies of the pathogenesis of status epilepticus failed to consider age-dependent mechanisms. Our previous studies focused on alterations in the surface expression and trafficking of the postsynaptic GABAA receptor population during status epilepticus. However, in ongoing studies characterizing chemoconvulsant-induced status epilepticus in animals younger than those used in the prior experiments, we observed a reduction in GABA-mediated inhibition that occurred in the absence of a postsynaptic modification in the GABAA receptor population. These studies suggest a novel central hypothesis that the reduction in the perisomatic inhibition of principal neurons in the hippocampus during status epilepticus in young animals is the result of a presynaptic modification in the release of GABA from basket cells. The proposed research focuses on providing a comprehensive mechanistic description of the changes in GABA-mediated inhibition that occur during status epilepticus at a stage of neurodevelopment at which status epilepticus commonly occurs in humans. We propose to test the predictions of our hypothesis by accomplishing 3 specific aims: (Aim 1) To demonstrate that the excitability of basket cells is decreased as the result of status epilepticus, (Aim 2) To demonstrate that the mean quantal content of GABA released from basket cells is decreased as the result of status epilepticus, and (Aim 3) To demonstrate that the postsynaptic modifications that occur during status epilepticus are age-dependent. An improved understanding of the factors that contribute to the dysfunction of GABAergic synaptic transmission during status epilepticus will provide a basis on which new rational therapies can be based. PUBLIC HEALTH RELEVANCE: These studies seek to understand the mechanisms underlying status epilepticus, prolonged seizures that predispose children and adults to death and long term neurological problems. Unfortunately, current medications used to treat these prolonged seizures sometimes fail. These studies will seek a new target for developing drugs for the treatment of this common neurological emergency.

描述（由申请人提供）：状态癫痫症的特征是长时间自我维持的癫痫发作，可以抵抗当前的第一线疗法。尽管它可以在任何年龄发生，但地位癫痫症是最常见的儿童神经系统紧急事件，尤其是1个月至4岁的年龄之间。幸运的是，对于某些儿童，癫痫持续状态不会产生任何后果。对于其他人来说，它与死亡或长期神经功能障碍有关。由于预后取决于持续时间，因此需要改善癫痫持续治疗的治疗方法。尽管同意，GABA介导的突触传播的修饰导致了癫痫持续状态的发病机理，但我们对基于此过程的细胞机制的理解尚不完整。而且，许多先前关于状态发病机理的实验室研究未能考虑年龄依赖性机制。我们以前的研究集中在癫痫持续性期间突触后GABAA受体人群的表面表达和运输的改变。然而，在正在进行的研究中，表征了比先前实验中使用的动物中化学弹药诱导的癫痫持续状态的癫痫持续性，我们观察到在GABAA受体人群中没有突触后修饰的情况下，GABA介导的抑制作用降低。这些研究表明，一个新的中心假设是，在年轻动物状态癫痫持续性期间，海马中主要神经元的临界抑制作用减少是由于篮细胞从篮细胞释放GABA时突触前修饰的结果。拟议的研究重点是提供对GABA介导的抑制变化的全面机械描述，而GABA介导的抑制作用在神经发育阶段发生的癫痫持续性抑制作用通常发生，在该阶段，在人类中通常发生癫痫持续状态。 We propose to test the predictions of our hypothesis by accomplishing 3 specific aims: (Aim 1) To demonstrate that the excitability of basket cells is decreased as the result of status epilepticus, (Aim 2) To demonstrate that the mean quantal content of GABA released from basket cells is decreased as the result of status epilepticus, and (Aim 3) To demonstrate that the postsynaptic modifications that occur during status epilepticus are age-dependent.对癫痫持续状态期间GABA能突触传播功能障碍的因素的改进理解将为新的理性疗法可以基于的基础提供基础。公共卫生相关性：这些研究试图了解癫痫持续状态的机制，长期癫痫发作，使儿童和成人易于死亡以及长期神经问题。不幸的是，当前用于治疗这些长时间癫痫发作的药物有时会失败。这些研究将寻求开发药物治疗这种常见神经系统紧急情况的新靶标。