Identifying neurons and circuits critical for epileptogenesis

描述(申请人提供)：根据世界卫生组织(WHO)的数据，全球有超过5000万人患有癫痫。这种大脑疾病不仅影响患者，还影响他们的家人，并间接影响整个社区。美国约有250万癫痫患者，每年增加150-20万例，构成每年约140亿美元的经济负担。颞叶癫痫(TLE)是最常见的耐药癫痫，由于反复发作和不可预测的发作，其发病率和死亡率很高。在平民人口中，在生命早期发生神经侮辱(头部创伤、癫痫持续状态、中风、炎症等)之间有很好的相关性。TLE的发展经历了一个“潜伏期”。除了平民，从伊拉克和阿富汗归来的美国退伍军人中创伤后癫痫的发生率可能会急剧增加，因为来自简易爆炸装置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，有61%的回国士兵脑损伤暴露在爆炸中，随后的创伤后癫痫很可能在这一人群中达到前所未有的比例。从脑损伤到慢性癫痫的转变称为癫痫发生。在缺乏对癫痫发生的机械性见解的情况下，也没有合理的药理学方法来预防癫痫。传统的抗癫痫药物(AED)在防止突然侮辱后将正常大脑转变为癫痫大脑方面无效。本提案将通过研究三种不同类型的大脑侮辱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主要认识空白。它将识别特定的神经元和电路，并将测试这些神经元元素是否对于在各种侮辱后发展为TLE是必要的和充分的。已经有一些间接证据表明，成年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是一群齿状回颗粒细胞，这些细胞在大脑发育最具可塑性的阶段被大脑侮辱“抓住”，从而导致了突发性脑损伤后的TLE。这构成了一个新的癫痫发生的概念模型，并且可以使用创新的光遗传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灭活特定神经元，从而完全可检验。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属性。然后，他们特定的“指纹”可以被用来开发新的药理或基因治疗工具，以阻止这些关键的神经成分在大脑受到侮辱后产生慢性癫痫。这些新发现将有助于将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.