Identifying neurons and circuits critical for epileptogenesis

描述（由申请人提供）：根据世界卫生组织（WHO），癫痫影响全球超过5000万人。这种脑部疾病不仅影响患者，还影响他们的家庭，并间接影响整个社区。美国约有250万癫痫患者，每年增加150- 200，000例，每年造成约140亿美元的经济负担。颞叶癫痫（TLE）是最常见的药物抵抗性癫痫，由于反复发作和不可预测的癫痫发作，与显著的发病率和死亡率相关。在平民人群中，生命早期神经系统损伤（头部创伤、癫痫持续状态、中风、炎症等）的发生与死亡之间存在良好的相关性。以及TLE经过“潜伏期”后的发展。除平民外，从伊拉克和阿富汗返回的美国退伍军人中创伤后癫痫的发病率可能急剧增加，因为简易爆炸装置产生的冲击波会产生一种新型的脑损伤，包括血管损伤。有证据表明，61%的退伍军人暴露于爆炸中，随后的创伤后癫痫在这一人群中可能达到前所未有的比例。从脑损伤到慢性癫痫的转变被称为癫痫发生。在缺乏癫痫发生机制的见解，没有合理的药理学方法来预防。传统的抗癫痫药物（AED）在预防突发性损伤后正常大脑转化为癫痫大脑方面是无效的。目前的建议将通过检查三种不同类型的脑损伤在细胞和电路水平上的共同潜在机制，来解决我们对癫痫发生过程的认识中的主要空白。它将识别特定的神经元和回路，并将测试这些神经元元素是否是必要的和足够的进展，以颞叶癫痫后，各种侮辱。已经有一些间接证据表明，成年人大脑中出生的神经元参与了这一过程。我们的中心假设是，癫痫发生的关键因素，导致TLE后沉淀脑损伤，是一组齿状回颗粒细胞，“抓住”的侮辱，在最具可塑性的发展阶段。这构成了癫痫发生的新概念模型，并且使用创新的新型光遗传学和化学分子生物学方法在癫痫发生过程中的特定时间激活或抑制特定神经元是完全可测试的。此外，电生理学和药理学研究将确定这些细胞和电路的区别特性。然后，它们的特定“指纹”可以用于开发新的药理学或基因治疗工具，这些工具将阻止这些关键的神经元素在大脑损伤后产生慢性癫痫。这些新发现将促进我们的基本发现转化为临床实践。

DESCRIPTION (provided by applicant): According to the World Health Organization (WHO), epilepsies affect over 50 million people worldwide. This brain disorder affects not only the sufferers but also their families and indirectly the entire community. The approximately 2.5 million epileptics in the US, with 150-200,000 cases added each year, constitute an annual economic burden of ~$14 billion. Temporal lobe epilepsy (TLE) is the most common form of pharmaco- resistant epilepsies and is associated with significant morbidity and mortality due to recurrent and unpredictable seizures. In the civilian population, there is a good correlation between the occurrence of a neurological insult earlier in life (head trauma, status epilepticus, stroke, inflammation, etc.) and the development of TLE after a "latent period". In addition to civilians, the incidence of posttraumatic epilepsy may increase drastically in the returning US veterans from Iraq and Afghanistan because the shock wave originating from Improvised Explosive Devices produces a novel type of brain injury including vascular damage. With evidence of brain injury in 61% of returning soldiers exposed to blasts, subsequent posttraumatic epilepsy is likely to reach unprecedented proportions in this population. The transition from brain insult to chronic epilepsy is termed epileptogenesis. In the absence of mechanistic insights into epileptogenesis, there is no rational pharmacological approach to its prevention. Conventional antiepileptic drugs (AEDs) are ineffective in preventing the conversion of a normal brain into an epileptic brain following a precipitating insult. The present proposal will address the major gap in our knowledge about the process of epileptogenesis by examining the common underlying mechanism at the cellular and circuit level of three different types of insult to the brain. It will identify specific neurons and circuits, and it will test whether these neuronal elements are necessary and sufficient for the progression to TLE following various insults. There is already some circumstantial evidence that neurons born in the adult brain are involved in this process. Our central hypothesis is that the key elements in epileptogenesis, leading to TLE following a precipitating brain insult, are a group of dentate gyrus granule cells that were "caught" by the insult at the most plastic stage of their development. This constitutes a new conceptual model of epileptogenesis and is fully testable using innovative novel optogenetic and chemical-molecular biological approaches to activate or inactivate specific neurons at specific times during the process of epileptogenesis. Moreover, electrophysiological and pharmacological studies will identify the distinguishing properties of these cells and circuits. Their specific "fingerprints" can then be used to develop novel pharmacological or gene therapy tools that will stop these critical neural elements from producing chronic epilepsy after a brain insult. The new discoveries will facilitate the translation of our basic findings into clinical practice.