The Role of Adult-born Dentate Granule Cells in Epileptogenesis

项目摘要 9%的人在一生中的某个时候会经历癫痫发作，但只有 这些患者中的一小部分将发展为癫痫，一种经常性无端癫痫发作的疾病。理解 为什么有些病人有癫痫发作的倾向增加，以及如何扭转这种趋势是至关重要的。 超过三分之一的癫痫患者药物治疗失败。此外，虽然有效减少 癫痫发作时，几乎没有证据表明这些疗法对癫痫发生有任何影响。此外，目前 诊断方式缺乏空间分辨率和特异性，无法准确识别和治疗脑区 与癫痫发生有关手术切除假定的癫痫组织有时会失败， 产生癫痫发作自由，并可能导致脑功能受损。虽然取得了重大进展， 虽然在癫痫的治疗中取得了进展，但对其发病机制的认识有限， 开发更复杂的疗法。 内侧颞叶癫痫（mTLE）是成人中最常见的癫痫形式， 其特征在于内侧颞叶边缘区域内的癫痫发作活动和病理，包括 海马结构mTLE的病理变化在齿状回中特别突出，这是一个关键的 控制海马体活动的节点，哺乳动物大脑中仅有的两个区域之一， 新的神经元在成年期产生。这些新生的齿状颗粒细胞与其他细胞连接， 神经元在现有的网络，似乎是重要的形成新的记忆，并经历了一些 mTLE的解剖学变化。然而，新生神经元的功能及其在海马中的作用 功能和癫痫发生尚不清楚。 这项研究将使用新型的深层双光子钙离子成像技术来探索 新生的齿状颗粒细胞如何募集抑制性神经元来平息海马体中的活动， 癫痫改变了这一过程。这些目标反映了我的长期职业目标，即开发基于干细胞的 旨在抑制兴奋性和逆转癫痫发生的疗法，以及工程细胞， 人类癫痫患者神经活动的光学报告者。这一指导奖将提供具体 神经干细胞、实验性癫痫模型和体内双光子显微镜的高级培训。这 培训将在神经干细胞和神经发生的领导者Fred Gage博士的指导下进行。 Drs. Tuszynski，Albergui和Barba将在转化神经科学和癫痫方面提供额外的指导， 确保我的职业发展不偏离正轨我们一起制定了详细的职业生涯 发展计划通过定期的导师会议、精心挑选的课程作业提供培训， 研讨会和实践研究经验。拟议的研究和职业发展计划将 从UCSD和索尔克研究所丰富的知识和协作环境中受益匪浅。

PROJECT SUMMARY Nine percent of the population will experience a seizure at some point in their lifetime, but only a fraction of these patients will develop epilepsy, a disease of recurrent unprovoked seizures. Understanding why some patients have an increased propensity for seizures and how to reverse this tendency is essential. More than a third of patients with epilepsy fail pharmacological therapy. Also while effective at decreasing seizures, there is little evidence that these therapies have any effect on epileptogenesis. Moreover, current diagnostic modalities lack the spatial resolution and specificity to accurately identify and treat brain areas involved in epileptogenesis. Surgical treatments removing putative epileptic tissue can sometimes fail to produce seizure freedom and can result in impairment of brain function. Thus, while significant progress has been made in the treatment of epilepsy, limited knowledge regarding its pathogenesis has precluded the development of more sophisticated therapies. Mesial temporal lobe epilepsy (mTLE) is the most common form of epilepsy in adults, and is characterized by seizure activity and pathology within the medial temporal limbic regions, including the hippocampal formation. Pathological changes in mTLE are particularly prominent in the dentate gyrus, a critical node for controlling activity in the hippocampus, and one of only a two regions in the mammalian brain where new neurons are born during adulthood. These newborn dentate granule cells make connections to other neurons in the existing network, appear to be important for forming new memories, and undergo an number of anatomical changes in mTLE. However, the function of newborn neurons and their role in hippocampal function and epileptogenesis are not known. Studies in this grant will employ the use of novel deep two photon Ca2+ imaging techniques to explore how newborn dentate granule cells recruit inhibitory neurons to quiet activity in the hippocampus, and how seizures alter this process. These aims reflect my long-term career objectives to develop stem cell-based therapies designed to quiet excitability and reverse epileptogenesis, as well as to engineer cells that express optical reporters of neural activity in human epileptic patients. This mentored award will provide specific advanced training in neural stem cells, experimental epilepsy models, and in vivo two-photon microscopy. This training will be conducted under the direction of Dr. Fred Gage, a leader in neural stem cells and neurogenesis. Drs. Tuszynski, Iragui, and Barba will provide additional mentoring in translational neuroscience and epilepsy, and ensure that I remain on track for career advancement. Together we have formulated a detailed career development plan providing training through regular mentor meetings, carefully selected coursework, seminars, and hands-on research experience. The proposed research and career development plan will benefit greatly from the intellectually rich and collaborative environments at UCSD and the Salk Institute.