An Interneuron-based Cell Therapy for Epilepsy

描述(由申请人提供)：神经前体细胞的移植提高了对神经疾病治疗的巨大期望。最近的一些研究，包括我们实验室的研究(Wichertle等人)。1999年；Alvarez-Dolado等人。2006)，证明了来自胚胎内侧神经节隆起(MGE)的移植前体细胞具有独特的分散、迁移和分化为GABA能中间神经元的能力。尽管我们最近证明了这些细胞在癫痫突变小鼠模型中抑制自发性癫痫发作是有效的(Baraban等人。2009年)，这种方法的治疗潜力在很大程度上仍未被发掘。为了回应最近NINDS癫痫研究的“基准”，我们建议进行实验，开发一种成人移植策略，使用从小鼠胚胎或从小鼠胚胎干细胞获得的MGE祖细胞。这些细胞将在自发性癫痫发作出现后移植到常见的颞叶癫痫啮齿动物模型中。技术将包括使用在体外保存的急性脑片，以及应用可视化膜片钳方法来研究MGE来源的中间神经元的功能整合。视频脑电监测和免疫荧光技术也将被应用。提出了三个具体的目标：(I)开发、优化和验证成年小鼠海马区MGE前体细胞移植的方法(Ii)检测成年MGE前体细胞移植在小鼠颞叶癫痫模型中的治疗潜力，以及(Iii)从小鼠胚胎干细胞建立MGE前体细胞系。我们的结果有望为成年宿主大脑中移植的MGE前体细胞的功能提供新的信息，并可能直接证明前体细胞治疗癫痫的潜力。

DESCRIPTION (provided by applicant): Transplantation of neural progenitor cells raises great expectations for the treatment of neurological disorders. A number of recent studies, including those from our laboratory (Wichertle et al. 1999; Alvarez-Dolado et al. 2006), demonstrate that transplanted progenitor cells derived from the embryonic medial ganglionic eminence (MGE) possess a unique ability to disperse, migrate, and differentiate into GABAergic interneurons. Although we recently demonstrated that these cells are effective in suppressing spontaneous seizures in a mutant mouse model of epilepsy (Baraban et al. 2009), the therapeutic potential of this approach remains largely unexplored. In response to recent NINDS epilepsy research "benchmarks", we here propose experiments to develop an adult transplantation strategy using MGE progenitors harvested from mouse embryos or derived from mouse embryonic stem cells. These cells will be transplanted in a common rodent model of temporal lobe epilepsy after the emergence of spontaneous seizures. Techniques will involve use of acute brain slices maintained in vitro, and application of visualized patch clamp methods to study the functional integration of MGE-derived interneurons. Video-EEG monitoring and immunofluorescence techniques will also be applied. Three specific aims are proposed: (i) to develop, optimize, and validate a method for transplantation of MGE progenitor cells in the adult mouse hippocampus (ii) to examine the therapeutic potential of adult MGE progenitor cell grafts in a mouse model of temporal lobe epilepsy, and (iii) to develop an MGE progenitor cell line from mouse embryonic stem cells. Our results promise to provide new information about the function of transplanted MGE progenitors in the adult host brain and may provide a direct demonstration of the potential for progenitor cells to treat epilepsy.