Respiration and Generalized Epilepsies

项目摘要 棘波放电（SWDs）是遗传性全身性癫痫（GGEs）中常见的一种发作类型。 过度换气在绝大多数失神癫痫患者中触发SWD， 常见的小儿GGE。我们最近开发了一种啮齿类动物癫痫模型，其中我们可以唤起 呼吸过度的突发性SWDs。在过度换气的6分钟内，SWD计数增加超过500%。 现在，我们利用这一模式，以前所未有的方式访问核心业务生成机制， 与SWDs 通过结合单个动物的体积描记法，EEG和血液测量，我们表明SWD电路 似乎对血液pH值非常敏感。首先，我们表明，缺氧，一种激活换气过度的条件， 很容易让人联想到啮齿动物的SWD缺氧引起的过度换气导致CO2呼出增加， 伴随血液碱化（即呼吸道碱化）。我们还表明，缺氧诱发的SWDs是 当大气CO2浓度升高时，血液碱性化被消除，从而支持血液碱性化驱动的假设。 过度通气诱发的SWD。最后，我们还表明，过度通气的光遗传学激活在 正常的大气条件-一个实验过程，减少血液二氧化碳，但增加氧气-也 引起了社会福利署的注意因此，我们的数据显示，SWD似乎主要与血液CO2协变。 我们用脑切片电生理学和钙成像来补充我们的体积描记-EEG数据。我们 将我们的注意力集中在丘脑的板内核上， 方法（即cFos）在缺氧诱导的过度通气后一致地标记该区域内的细胞。通过使用 全细胞膜片钳记录技术，我们证明，板内丘脑细胞产生 在碱化条件下去极化离子电流。这股电流的很大一部分似乎是由 通过增强兴奋性突触驱动 通过我们的初步数据，我们现在提出了一个项目，旨在测试总体假设，即激活 急性呼吸衰竭引起的丘脑板内神经元pH敏感性沉淀缺失 癫痫发作识别这些神经元及其激活机制将为治疗脑梗死的新策略提供信息。 最常见的儿科胃肠道疾病，即仅存在数十年历史的次优治疗方法的疾病。我们 具体检验以下主要假设： 目的1呼吸道痉挛引发失神发作。 目的2自发性和过度换气触发性癫痫发作利用相同的神经回路。 当完成时，我们希望我们的项目结果将为基础知识提供重要的新见解。 细胞和电路水平的机制，驱动广义尖峰波放电，因此铺平了新的 癫痫病的治疗方法

Project Summary Spike-Wave Discharges (SWDs) are a common type of seizure in the Genetic Generalized Epilepsies (GGEs). Hyperventilation triggers SWDs in the overwhelming majority of patients with absence epilepsy, the most common form of pediatric GGE. We have recently developed a rodent epilepsy model wherein we can evoke a burst of SWDs with hyperventilation. Within 6 minutes of hyperventilation, SWD count increases by over 500%. We now leverage this model to gain unprecedented access to core seizure-generating mechanisms associated with SWDs. By combining plethysmography, EEG and blood measurements in single animals, we show that SWD circuits appear critically sensitive to blood pH. First, we show that hypoxia, a condition that activates hyperventilation, robustly evokes rodent SWDs. Hypoxia-induced hyperventilation results in increased exhalation of CO2 and concomitant blood alkalization (i.e. respiratory alkalosis). We also show that hypoxia-evoked SWDs are abolished when atmospheric CO2 is elevated, thereby supporting the hypothesis that blood alkalization drives hyperventilation-evoked SWDs. Finally, we also show that optogenetic activation of hyperventilation during normal atmospheric conditions – an experimental procedure that reduces blood CO2 but increases O2 – also evokes SWDs. Thus, collectively our data show that SWDs appear to primarily covary with blood CO2. We complement our plethysmography-EEG data with brain slice electrophysiology and calcium imaging. We focus our attention on the intralaminar nuclei of the thalamus because activity-dependent cell tagging approaches (i.e. cFos) consistently label cells within this region after hypoxia-induced hyperventilation. By using whole-cell patch clamp recording techniques we demonstrate that intralaminar thalamic cells produce depolarizing ionic currents during alkalized conditions. A significant portion of this current appears to be mediated by enhanced excitatory synaptic drive. With our preliminary data, we now present a project that aims to test the overarching hypothesis that activation of pH-sensitive intralaminar thalamic neurons by acute respiratory alkalosis precipitates absence seizures. Identifying these neurons and their mechanisms of activation will inform new strategies to treat the most common pediatric GGEs, disorders for which only decades-old, sub-optimal treatments exist. We specifically test the following main hypotheses:  Aim 1 Respiratory alkalosis triggers absence seizures.  Aim 2 Spontaneous and hyperventilation-triggered seizures utilize the same neural ciruitry. When complete, we expect that the results of our project will provide significant, new insights into fundamental cellular- and circuit-level mechanisms that drive generalized spike-wave discharges, and therefore pave new avenues for generalized epilepsy treatments.