Mechanisms compromising GABAergic synaptic transmission during status epiletpicus

描述（由申请方提供）：癫痫持续状态的特征是持续时间长、自我持续的癫痫发作，可能对当前一线治疗具有抵抗力。虽然它可以发生在任何年龄，癫痫持续状态是儿童最常见的神经系统急症，特别是在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没有后果。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。尽管一致认为GABA介导的突触传递的改变有助于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，许多先前的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。我们以前的研究集中在癫痫持续状态期间突触后GABAA受体群体的表面表达和运输的改变。然而，在正在进行的研究中，化学惊厥诱导的癫痫持续状态的动物比以前的实验中使用的，我们观察到减少GABA介导的抑制，发生在GABAA受体群体的突触后修饰的情况下。这些研究提出了一个新的中心假说，即在年轻动物癫痫持续状态期间海马中的主要神经元的体周抑制的减少是从篮状细胞释放GABA的突触前修饰的结果。拟议的研究重点是提供一个全面的机制描述GABA介导的抑制，发生在癫痫持续状态的神经发育阶段，癫痫持续状态通常发生在人类。我们建议通过实现3个具体目标来测试我们假设的预测：（目的1）证明篮细胞的兴奋性由于癫痫持续状态而降低，（目的2）证明从篮细胞释放的GABA的平均量子含量由于癫痫持续状态而降低，（目的3）证明癫痫持续状态时发生的突触后修饰具有年龄依赖性。对癫痫持续状态期间GABA能突触传递功能障碍的因素的进一步了解将为新的合理治疗提供基础。 公共卫生相关性：这些研究试图了解癫痫持续状态的潜在机制，长期癫痫发作使儿童和成人易于死亡和长期神经系统问题。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。这些研究将为开发治疗这种常见神经系统紧急情况的药物寻找新的靶点。

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.