Rewiring the Injured Brain with GABA Progenitors

摘要 神经前体细胞移植在许多神经系统的治疗方面具有非凡的潜力。 精神错乱。最近的几项研究表明，祖细胞来源于胚胎小鼠的内侧 神经节隆起具有向GABA能中间神经元迁移和分化的独特能力 移植到幼年或成年啮齿类动物的大脑中。我们最近证明了这些细胞是 有效纠正小鼠记忆障碍和预防自发性癫痫发作 创伤性脑损伤。然而，目前还不清楚是否可以达到类似的治疗效果。 临床相关的细胞来源，如人类多能干细胞。在这里，我们建议进行研究，以评估 人源性中间神经元在创伤性脑损伤临床前模型中的作用。我们的方法包括 人神经间神经前体细胞移植到广泛使用的闭合性脑损伤啮齿动物模型中 损伤后不同阶段的体外膜片钳记录、免疫荧光技术 神经回路标测以评估移植神经元的突触整合。一连串的行为 分析和视频脑电监测也将被应用。提出了两个具体目标：(1)确定如何 人源性GABA前体细胞整合到脑损伤的海马区，以及(Ii)测试治疗 人GABA神经元在小鼠创伤性脑损伤模型中的疗效。如果成功，我们的结果将有所帮助 通过为人类建立相对直接的概念证明，将这些令人兴奋的技术更接近临床 神经元间移植治疗创伤性脑损伤

Abstract Transplantation of neural progenitor cells has extraordinary potential for the treatment of many nervous system disorders. Several recent studies have shown that progenitor cells derived from the embryonic mouse medial ganglionic eminence (MGE) retain a unique ability to migrate and differentiate into GABAergic interneurons following transplantation into the juvenile or adult rodent brain. We recently demonstrated that these cells are effective in correcting memory impairments and preventing spontaneous seizures in a mouse model of traumatic brain injury. However, it is not known whether similar therapeutic effects can be achieved with clinically-relevant cell sources, such as human pluripotent stem cells. Here, we propose studies to evaluate the effect of human-derived interneurons in a pre-clinical model of traumatic brain injury. Our approach involves transplantation of human interneuron progenitors into a widely-used rodent model of closed-head injury at different stages following injury followed by in vitro patch-clamp recordings, immunofluorescence techniques and neural circuit mapping to evaluate the synaptic integration of grafted neurons. A battery of behavioral assays and video-EEG monitoring will also be applied. Two specific aims are proposed: (i) determine how human-derived GABA progenitors integrate into brain injured hippocampus, and (ii) test the therapeutic efficacy of human GABA neurons in a mouse model of traumatic brain injury. If successful, our results will help move these exciting technologies closer to the clinic by establishing relatively direct proof of concept for human interneuron transplantation to treat traumatic brain injury.