The Role of Adult-born Dentate Granule Cells in Epileptogenesis

项目总结 9%的人会在一生中的某个时候经历癫痫发作，但只有 这些患者中的一小部分会患上癫痫，这是一种反复发作的无缘无故的疾病。理解 为什么一些患者癫痫发作的倾向增加，以及如何扭转这一趋势是至关重要的。 超过三分之一的癫痫患者未能通过药物治疗。此外，虽然在减少 对于癫痫发作，几乎没有证据表明这些疗法对癫痫的发生有任何影响。此外，目前 诊断模式缺乏空间分辨率和特异性，无法准确识别和治疗大脑区域 与癫痫的发生有关。切除疑似癫痫组织的外科治疗有时会失败 产生癫痫自由，并可能导致大脑功能受损。因此，在取得重大进展的同时， 虽然在治疗癫痫方面取得了一些进展，但对其发病机制的了解有限，阻碍了 开发更复杂的治疗方法。 内侧颞叶癫痫(MTLE)是成人最常见的癫痫形式， 以内侧颞叶边缘区域的癫痫活动和病理为特征，包括 海马体结构。MTLE的病理改变在齿状回尤为突出，这是一种关键的 控制海马体活动的节点，也是哺乳动物大脑中仅有的两个区域之一 新的神经元是在成年期诞生的。这些新生的齿状颗粒细胞与其他 现有网络中的神经元似乎对形成新的记忆很重要，并经历了许多 MTLE的解剖学改变。然而，新生神经元的功能及其在海马区的作用 其功能和癫痫发生机制尚不清楚。 这项资助的研究将使用新的深双光子钙离子成像技术来探索 新生齿状颗粒细胞如何招募抑制神经元来抑制海马区的活动，以及如何 癫痫发作改变了这一过程。这些目标反映了我开发以干细胞为基础的长期职业目标 旨在抑制兴奋性和逆转癫痫发生的治疗方法，以及改造细胞表达 人类癫痫患者神经活动的光学记录器。这一指导奖将提供具体的 神经干细胞、实验性癫痫模型和活体双光子显微镜方面的高级培训。这 培训将在弗雷德·盖奇博士的指导下进行，弗雷德·盖奇博士是神经干细胞和神经发生领域的领军人物。 图辛斯基、伊拉吉和巴尔巴博士将在翻译神经科学和癫痫方面提供额外的指导， 并确保我继续保持在职业发展的轨道上。我们共同制定了一份详细的职业生涯 发展计划，通过定期导师会议提供培训，精心挑选课程， 研讨会和实践研究经验。拟议的研究和职业发展计划将 从加州大学圣地亚哥分校和索尔克研究所丰富的智力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.