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

• 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
• 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

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）：癫痫持续状态的特点是持续性的长期癫痫发作，对当前的一线治疗可能产生耐药性。尽管癫痫持续状态可以发生在任何年龄，但它是儿童期最常见的神经急症，尤其是 1 个月至 4 岁之间。幸运的是，对于一些儿童来说，癫痫持续状态的发生不会产生任何后果。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，因此需要改进癫痫持续状态的治疗方法。尽管人们一致认为 GABA 介导的突触传递的改变会导致癫痫持续状态的发病机制，但我们对这一过程背后的细胞机制的理解并不完整。而且，许多先前关于癫痫持续状态发病机制的实验室研究未能考虑年龄依赖性机制。我们之前的研究重点是癫痫持续状态期间突触后 GABAA 受体群体表面表达和运输的变化。然而，在正在进行的研究中，在比先前实验中使用的动物更年轻的动物中表征化学惊厥诱发的癫痫持续状态，我们观察到在 GABAA 受体群体中没有突触后修饰的情况下，GABA 介导的抑制作用减少。这些研究提出了一个新的中心假设，即幼年动物癫痫持续状态期间海马主要神经元的体周抑制减少是篮子细胞释放 GABA 的突触前修饰的结果。拟议的研究重点是对在人类癫痫持续状态常见的神经发育阶段发生的癫痫持续状态期间发生的 GABA 介导的抑制变化提供全面的机制描述。我们建议通过实现 3 个具体目标来检验我们假设的预测：（目标 1）证明篮子细胞的兴奋性因癫痫持续状态而降低，（目标 2）证明篮子细胞释放的 GABA 平均量子含量因癫痫持续状态而降低，以及（目标 3）证明癫痫持续状态期间发生的突触后修饰具有年龄依赖性。更好地了解导致癫痫持续状态期间 GABA 能突触传递功能障碍的因素将为新的合理治疗奠定基础。 公共卫生相关性：这些研究旨在了解癫痫持续状态、导致儿童和成人死亡的长期癫痫发作以及长期神经系统问题的潜在机制。不幸的是，目前用于治疗这些长期癫痫发作的药物有时会失败。这些研究将寻找新的目标来开发治疗这种常见神经系统紧急情况的药物。

项目成果

The pervasive reduction of GABA-mediated synaptic inhibition of principal neurons in the hippocampus during status epilepticus.

癫痫持续状态期间海马主要神经元 GABA 介导的突触抑制普遍减少。

• DOI: 10.1016/j.eplepsyres.2015.11.006
• 发表时间: 2016
• 期刊: Epilepsy research
• 影响因子: 2.2
• 作者: Sun,HuaYu;Goodkin,HowardP
• 通讯作者: Goodkin,HowardP