A novel target for seizure suppression in chronic temporal lobe epilepsy

项目摘要/摘要 100多万美国人患有颞叶癫痫。不幸的是，其中三分之一的人遭受 从无法控制的、医学上难以控制的癫痫发作中解脱出来。除了降低一个人的生活质量，不受控制 癫痫发作也极大地增加了癫痫猝死的风险。新疗法的发展 覆盖到更广泛的患者群体的选择将减少患上失控疾病的人数 癫痫发作。开发治疗颞叶癫痫的新疗法的一个重要步骤是了解 受影响区域的潜在神经回路。在颞叶癫痫中，最常见的发作灶是 海马体。目前的项目将探索几乎没有先验特征的抑制性细胞群体如何 在文献中符合健康和癫痫患者的海马神经回路。此外，该项目可能会确定一个 为患有内科疾病的患者开发新的有效治疗方案的候选目标 难治性颞叶癫痫。具体地说，该项目旨在检查这里所指的细胞群体 AS LINCS(或长程抑制性神经元型一氧化氮合酶(NNOS)表达细胞)。首先，在一只老鼠身上 慢性颞叶癫痫模型，我将检验Lincs是一个凝聚细胞群的假设 对健康和癫痫的海马体提供强大、持久和广泛的抑制。然后, 使用我的顾问之前开发的按需光遗传癫痫干预策略和 赞助Krook-Magnuson博士，我将测试Lincs能够缩短癫痫发作持续时间的假设， 频率和严重性。这个项目的结果将增加我们对健康的海马体电路的了解 并将说明癫痫大脑中的电路是如何改变的。此外，这项研究的结果可能 为新的抗癫痫治疗药物的开发确定新的靶点。通过建议的培训 在这里，我将获得在细胞和电路水平上研究神经紊乱所需的工具，并将 做好充分准备，迈向独立科学家职业生涯的下一步。

Project Summary/Abstract Over 1 million Americans suffer from temporal lobe epilepsy. Unfortunately, one third of those individuals suffer from uncontrolled, medically refractory, seizures. In addition to diminishing one’s quality of life, uncontrolled seizures also greatly increase the risk of sudden death from epilepsy. The development of new treatment options that reach a wider patient population will reduce the number of people suffering from uncontrolled seizures. An important step in developing new treatments for temporal lobe epilepsy is to understand the underlying neural circuitry of the effected region. Most often in temporal lobe epilepsy, the seizure focus is the hippocampus. The current project will explore how an inhibitory cell population with little prior characterization in the literature fits into the healthy and epileptic hippocampal circuitry. Furthermore, this project may identify a candidate target for the development of novel and efficacious treatment options for people with medically refractory temporal lobe epilepsy. Specifically, this project aims to examine a cell population hereby referred to as LINCs (or, long-range inhibitory neuronal nitric oxide synthase (nNOS)-expressing cells). First, in a mouse model of chronic temporal lobe epilepsy, I will test the hypothesis that LINCs are a cohesive cell population that provide strong, long-lasting, and widespread inhibition to the healthy and epileptic hippocampus. Then, using an on-demand optogenetic seizure intervention strategy previously developed by my advisor and sponsor Dr. Krook-Magnuson, I will test the hypothesis that LINCs are capable of reducing seizure duration, frequency, and severity. The results of this project will increase our knowledge of healthy hippocampal circuitry and will illustrate how that circuitry is altered in the epileptic brain. Additionally, the results of this study may identify a novel target for the development of new anti-seizure therapeutics. Through the training proposed here, I will gain the tools necessary to investigate neurological disorders at a cellular and circuit level and will be well-prepared to take the next steps towards a career as an independent scientist.