Validation of a novel mouse model of temporal lobe epilepsy

项目总结 这些研究的长期目标是为癫痫患者开发新的治疗方法，这些患者的癫痫发作 不能被现有的药物很好地控制(耐药)。这些患者中的许多人都有一种局灶性癫痫 称为颞叶癫痫(TLE)。在开发新的治疗方法方面进展甚微 这些患者因为缺乏合适的动物模型。目前的TLE模型显示出更大的神经元 在患者中观察到的死亡和海马体硬化，以及高度可变的癫痫发作发生率 排除了药物测试。拟议的研究将验证新的TLE小鼠模型的有用性 克服了这些问题。研究发现，一种特定品系小鼠的温和点燃方案VGAT- CRE，导致自发性癫痫发作。点燃指的是反复电刺激最终 引发强直阵挛发作。然而，点燃只会导致VGAT-CRE小鼠的自发癫痫发作。这些 小鼠在囊泡状GABA转运体(VGAT)的控制下表达Cre重组酶，VGAT是一种 在GABA能抑制神经元中特异表达。这些神经元的丢失或功能障碍 海马体与颞叶癫痫的发生有关。这项研究的第一个目的是 优化点燃方案，以产生用于药物测试的具有理想自发发作频率的小鼠。 第二个目标是验证这些小鼠对目前可用的抗癫痫药物的反应。这项工作将是 由犹他大学的Wilcox博士的团队完成，他也是NIH赞助的癫痫治疗的负责人 筛查计划。

Project summary The long-term goal of these studies is to develop novel therapeutics for epilepsy patients whose seizures are not well-controlled by current drugs (pharmacoresistant). Many of these patients have a type of focal epilepsy called temporal lobe epilepsy (TLE). There has been little progress in the development of novel therapies for these patients because of the lack of suitable animal models. Current TLE models show much greater neuronal death and hippocampal sclerosis than observed in patients, and a highly variable occurrence of seizures that precludes drug testing. The proposed studies will validate the usefulness of new mouse model of TLE that overcomes these problems. It was discovered that a mild kindling protocol of a specific strain of mice, VGAT- Cre, led to spontaneous seizures. Kindling refers to the process where repeated electrical stimulations eventually trigger tonic-clonic seizures. However, kindling only leads to spontaneous seizures in VGAT-Cre mice. These mice express Cre recombinase under the control of the vesicular GABA transporter (VGAT), a gene that is specifically expressed in GABAergic inhibitory neurons. Loss, or dysfunction, of these neurons in the hippocampus has been linked to the development of temporal lobe epilepsy. The first aim of this study will optimize kindling protocols to generate mice with an ideal frequency of spontaneous seizures for drug testing. The second aim is to validate that these mice respond to currently available antiseizure drugs. This work will be done by Dr. Wilcox’s group at the University of Utah, who also directs the NIH-sponsored Epilepsy Therapy Screening Program.