Mechanisms compromising GABAergic synaptic transmission during status epiletpicus

描述（由申请人提供）：癫痫持续状态的特征是长时间的、自我持续的癫痫发作，可能对目前的一线治疗产生耐药性。虽然它可以发生在任何年龄，但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，对一些儿童来说，癫痫持续状态没有任何后果。对其他人来说，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，因此需要改进治疗癫痫持续状态的方法。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尚不完整；而且，许多先前的实验室研究癫痫持续状态的发病机制未能考虑到年龄依赖的机制。我们之前的研究主要集中在癫痫持续状态下突触后GABAA受体群体的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化学惊厥药诱导的癫痫持续状态中，我们观察到gaba介导的抑制减少，这种抑制发生在GABAA受体群体中缺乏突触后修饰的情况下。这些研究提出了一个新的中心假设，即幼龄动物癫痫持续状态期间海马主要神经元的突触周围抑制的减少是篮状细胞释放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，在癫痫持续状态的神经发育阶段发生的gaba介导的抑制的变化，在癫痫持续状态通常发生在人类。我们建议通过实现三个特定目标来验证我们假设的预测：（目标1）证明篮状细胞的兴奋性因癫痫持续状态而降低；（目标2）证明篮状细胞释放的GABA的平均量含量因癫痫持续状态而降低；（目标3）证明癫痫持续状态期间发生的突触后修饰是年龄依赖性的。进一步了解导致癫痫持续状态中gaba能突触传递功能障碍的因素将为新的合理治疗提供基础。

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.