Contributions of aberrant granule cell integration to the development of epilepsy

描述（由申请人提供）：颞叶癫痫是一种严重的疾病，没有预防和治疗。此外，现有的治疗方法往往无效，药物副作用可能很严重，特别是在儿童中。为了开发更好的治疗方法，我们试图了解正常的大脑是如何变得癫痫的。阐明癫痫发生的机制将被证明是治疗并最终治愈这种疾病的关键。神经科学的最新进展表明，成年人会产生新的脑细胞。虽然这些新的脑细胞可能在健康人类中发挥重要作用，但我们认为这些新细胞的异常发育和整合有助于癫痫的发展。为了确定成人产生的脑细胞是否应该成为开发癫痫新疗法的目标，我们开发了一种小鼠模型系统，使我们能够比较癫痫发展过程中现有和新产生的脑细胞的结构。这些研究将确定新细胞是否选择性地容易受到可能促进癫痫的变化的影响。初步研究证实，新生细胞发展出癫痫大脑的标志性病理，而成熟细胞似乎不受影响。在第二组实验中，我们将研究癫痫发作对新脑细胞整合的影响。癫痫通常发生在神经损伤后，如头部创伤、缺氧或癫痫持续状态。新脑细胞的异常整合可能是这种初始损伤的直接后果。或者，最初的损伤可能导致自发性癫痫发作的发生，而这些癫痫发作反过来又可能破坏新细胞的整合。为了区分这些可能性，将在致癫痫性脑损伤后的几个月内评估小鼠的癫痫发作频率。损伤后产生的细胞形态将与这些动物中癫痫发作的存在和频率相关。重要的是，这项研究的结果将确定癫痫控制是否可能是促进新生儿脑细胞正确整合的有效靶点。最后，为了确定异常整合的新生儿脑细胞是否可以靶向治疗癫痫，我们将利用转基因小鼠模型，这将使我们能够选择性地消融癫痫脑中的新生儿细胞。这些研究将是第一个检查选择性消融癫痫大脑中任何异常细胞群的影响的研究，我们希望我们的研究结果将为开发新的更有效的癫痫治疗方法提供基础。公共卫生相关性：在成年人中，海马体每天都有新的脑细胞诞生，海马体是常见癫痫病发展的关键区域。这些新细胞的异常结合到大脑中可能会促进疾病的发展。该提案将阐明这些新神经元对癫痫病理、发育和维持的贡献。通过确定正常的大脑是如何变得癫痫的，我们可以开始开发治疗方法来延迟，停止并最终逆转这一过程。

DESCRIPTION (provided by applicant): Temporal lobe epilepsy is a serious disease for which there is no preventative and no cure. Moreover, available therapies are often ineffective, and medication side effects can be severe, particularly in children. In an effort to develop better treatments for the disease, we seek to understand how normal brains become epileptic. Elucidating the mechanisms of epileptogenesis will prove critical for treating, and ultimately curing, the disease. Recent advances in neuroscience have revealed that new brain cells are generated in adults. While these new brain cells likely play important roles in healthy humans, we believe that abnormal development and integration of these new cells contributes to the development of epilepsy. To determine whether adult-generated brain cells should be targeted for developing new treatments for epilepsy, we have developed a mouse model system which allows us to compare the structure of existing and newly-generated brain cells during the development of epilepsy. These studies will establish whether the new cells are selectively vulnerable to developing changes likely to promote epilepsy. Initial studies confirm the newborn cells develop hallmark pathologies of the epileptic brain, while mature cells appear unaffected. In a second set of experiments, we will examine the impact of seizures on the integration of new brain cells. Epilepsy frequently develops following neurological injuries such as head trauma, hypoxia or status epilepticus. Abnormal integration of new brain cells may result as a direct consequence of this initial injury. Alternatively, the initial injury may result in the occurrence of spontaneous seizures, and these seizures, in turn, may disrupt new cell integration. To distinguish between these possibilities, seizure frequency will be assessed in mice for several months following an epileptogenic brain insult. The morphology of cells born after the insult will be correlated with the presence and frequency of seizures in these animals. Importantly, the outcome of this study will determine whether seizure control might be an effective target for promoting the correct integration of newborn brain cells. Finally, to determine whether abnormally integrated newborn brain cells can be targeted to cure epilepsy, we will utilize a transgenic mouse model which will allow us to selective ablate newborn cells from the epileptic brain. These studies will be the first to examine the impact of selectively ablating any abnormal cell population from the epileptic brain, and it is our hope that our findings will provide the basis for developing new and more effective treatments for epilepsy. PUBLIC HEALTH RELEVANCE: In adults, new brain cells are born daily in the hippocampus, a region pivotal to the development of common forms of epilepsy. Abnormal incorporation of these new cells into the brain may promote the development of the disease. This proposal will elucidate the contribution of these new neurons to pathology, development and maintenance of epilepsy. By determining how normal brains become epileptic, we can begin to develop therapies to delay, halt and ultimately reverse the process.