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持续的、自我维持的发作，可以抵抗目前的一线治疗。虽然癫痫持续状态可以发生在任何年龄，但它是儿童最常见的神经紧急情况，特别是在1个月到4岁之间。幸运的是，对于一些儿童来说，癫痫持续状态是没有后果的。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，因此需要改进癫痫持续状态的治疗方法。尽管GABA介导的突触传递的修饰有助于癫痫持续状态的发病，但我们对这一过程背后的细胞机制的了解并不完整；而且，先前许多关于癫痫持续状态发病机制的实验室研究没有考虑年龄依赖的机制。我们以前的研究集中在癫痫持续状态期间突触后GABAA受体群体表面表达和运输的变化。然而，在正在进行的研究中，我们观察到在GABAA受体群体中，在缺乏突触后修饰的情况下，GABA介导的抑制减少。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时，海马区主神经元周围抑制的减少是突触前修饰从篮子细胞释放GABA的结果。这项拟议的研究侧重于对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，而癫痫持续状态通常发生在人类的神经发育阶段。我们建议通过实现三个特定目标来验证我们的假设：(目标1)证明癫痫持续状态导致篮子细胞的兴奋性降低，(目标2)证明癫痫持续状态导致篮子细胞释放的GABA的平均量子含量减少，(目标3)证明癫痫持续状态期间发生的突触后改变是年龄相关的。对癫痫持续状态时GABA能突触传递功能障碍因素的深入了解将为新的合理治疗提供依据。 公共卫生相关性：这些研究试图了解癫痫持续状态、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。这些研究将寻求开发治疗这种常见神经紧急情况的药物的新目标。

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.