The role of spreading depression in the development of chronic epilepsy

癫痫是一种使人衰弱的神经疾病，影响着全球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有不受控制的癫痫发作。大多数癫痫发作发生在所谓的结构性癫痫的框架内，这些癫痫是由于各种最初的脑损伤行为而发展起来的，如中风、颅内出血(ICB)或脑感染。结构性癫痫的最佳治疗方法将是预防。然而，我们对癫痫形成的潜在机制的了解，也就是癫痫发生的过程，仍然远未完成。有证据表明，在急性医疗条件下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研究(EEG)表明，癫痫发作往往还分别伴随着扩散性去极化和抑郁(SD)。SD构成了神经元近乎完全的去极化，导致细胞膜电位的崩溃，并在几分钟内连续抑制神经元的活动，最长可达几小时。尽管SD有很大的作用范围，但其致痫潜力仍然很不清楚。由于临床癫痫学中的脑电信号滤波标准，SD在临床脑电记录中甚至基本上是不可检测的。利用多模式实验平台，本项目将阐明SD在癫痫发生中的作用。为此，该项目将采用最近泰勒的小鼠脑脊髓炎病毒(TMEV)癫痫小鼠模型来模拟现实生活条件。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。结合神经网络动力学的慢性多区域钙成像(GCaMP)和自由活动小鼠的视频脑电监测，SD及其与癫痫发作的关联将在几个月的时间内具有高神经解剖学分辨率的特征，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式记录一起，在新皮质或海马区使用光纤引导的定时和区域特定的SD光遗传激发(C1V1，ChR2)。这将允许在存在或不存在脑部炎症过程的情况下，对SD的致痫潜力进行精确的机械性评估。该项目的结果可能导致临床癫痫学的范式转变，因为该领域普遍认为SD仅仅是癫痫发作的一种附带现象，几乎没有或根本没有改变疾病的潜力。此外，该项目可能会为预防结构性癫痫揭示新的治疗目标。

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.