The role of spreading depression in the development of chronic epilepsy

抑郁症扩散在慢性癫痫发展中的作用

• 批准号: 504342801
• 负责人: Privatdozent Dr. Michael Wenzel
• 金额: --
• 依托单位: Klinik für Epileptologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504342801?language=en
• 关键词: role; spreading; depression; development; chronic

Epilepsy is a debilitating neurological disorder affecting 50 million people worldwide. Despite a variety of medical treatment options, a third of epilepsy patients keep having uncontrolled seizures. Most epileptic seizures occur in the framework of so-called structural epilepsies that develop as a consequence of most varied initial brain- damaging insults such as stroke, intracranial bleeding (ICB), or brain infections. The optimal therapy of structural epilepsies would be their prevention. Yet, our knowledge of the mechanisms underlying the development of epilepsy, a process called epileptogenesis, has remained far from complete. There is evidence that seizures during acute medical conditions increase the risk of subsequent structural epilepsy. However, electroencephalographic studies (EEG) in the context of such conditions have shown that seizures are often also accompanied by spreading depolarizations, and depressions, respectively (SD). SD constitutes a near-complete depolarization of neurons leading to a breakdown of the cellular membrane potential, and consecutive depression of neuronal activity over minutes, up to hours. Despite its substantial effect size, the epileptogenic potential of SD has remained largely obscure. Due to EEG signal filtering standards in clinical epileptology, SD is even essentially undetectable in clinical EEG recordings. Using a multimodal experimental platform, this project will elucidate the role of SD in epileptogenesis. To this end, the project will employ the recent Theiler’s murine encephalomyelitis virus (TMEV) epilepsy mouse model mimicking real life conditions. The model encompasses epileptic seizures and SD during acute self-limiting encephalitis, and frequently develops into structural epilepsy. Combining chronic multi-region calcium imaging of neural network dynamics (GCaMP) with video-EEG monitoring in freely moving mice, SD and its association with seizures will be characterized at high neuroanatomical resolution across months, ranging from health to chronic epilepsy. Based on measured SD frequency and duration in a realistic disease setting, the project will, along with the mentioned multimodal recordings, employ fiber-guided timed and region-specific optogenetic elicitation (C1V1, ChR2) of SD in neocortex or hippocampus. This will allow a precise mechanistic evaluation of the epileptogenic potential of SD, in the presence or absence of brain inflammatory processes. The results of this project could lead to a paradigm shift in clinical epileptology, as the field widely views SD as a mere epiphenomenon of seizures with little or no disease modifying potential. Moreover, this project could potentially unveil new therapeutic targets for the prevention of structural epilepsies.

癫痫是一种使人衰弱的神经系统疾病，影响着全世界5000万人。尽管有各种各样的医疗选择，三分之一的癫痫患者仍然无法控制癫痫发作。大多数癫痫发作发生在所谓的结构性癫痫的框架内，这种癫痫是由各种各样的初始脑损伤（如中风、颅内出血或脑感染）引起的。治疗结构性癫痫的最佳方法是预防。然而，我们对癫痫发病机制的了解，一个被称为癫痫发生的过程，仍远未完成。有证据表明，急性疾病期间的癫痫发作会增加随后发生结构性癫痫的风险。然而，在这种情况下的脑电图研究（EEG）表明，癫痫发作通常还分别伴有扩张性去极化和抑郁（SD）。SD构成了神经元几乎完全的去极化，导致细胞膜电位的破坏，神经元活动在几分钟甚至几小时内持续下降。尽管SD具有显著的效应大小，但其致痫潜能在很大程度上仍不清楚。由于临床癫痫学的脑电图信号滤波标准，SD在临床脑电图记录中甚至基本无法检测到。利用多模态实验平台，本项目将阐明SD在癫痫发生中的作用。为此，该项目将采用最近的Theiler小鼠脑脊髓炎病毒（TMEV）癫痫小鼠模型模拟现实生活条件。该模型包括急性自限性脑炎期间的癫痫发作和SD，并经常发展为结构性癫痫。结合自由运动小鼠的慢性多区域神经网络动态钙成像（GCaMP）和视频脑电图监测，SD及其与癫痫发作的关系将在几个月内以高神经解剖学分辨率进行表征，范围从健康到慢性癫痫。基于在现实疾病环境中测量的SD频率和持续时间，该项目将与上述多模态记录一起，在新皮层或海马中使用纤维引导的定时和区域特异性SD光遗传激发（C1V1, ChR2）。这将允许在存在或不存在脑炎症过程的情况下，对SD的致痫潜能进行精确的机制评估。该项目的结果可能会导致临床癫痫学的范式转变，因为该领域广泛认为SD仅仅是癫痫发作的附带现象，几乎没有或根本没有改变疾病的潜力。此外，该项目可能会揭示预防结构性癫痫的新治疗靶点。