Rewiring the Injured Brain with GABA Progenitors

摘要 神经祖细胞移植在治疗许多神经系统方面具有非凡的潜力 失调。最近的几项研究表明，源自小鼠胚胎内侧的祖细胞 神经节隆起 (MGE) 保留了迁移和分化为 GABA 能中间神经元的独特能力 移植到幼年或成年啮齿动物大脑后。我们最近证明这些细胞 在小鼠模型中可有效纠正记忆障碍并预防自发性癫痫发作 脑外伤。然而，尚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，例如人类多能干细胞。在这里，我们提出研究来评估 人源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 将人类中间神经元祖细胞移植到广泛使用的闭合性头部损伤的啮齿动物模型中 损伤后的不同阶段，然后进行体外膜片钳记录、免疫荧光技术 和神经回路映射来评估移植神经元的突触整合。行为电池 检测和视频脑电图监测也将被应用。提出了两个具体目标：(i) 确定如何 人源性 GABA 祖细胞整合到脑损伤的海马体中，并且 (ii) 测试治疗效果 人类 GABA 神经元在小鼠脑外伤模型中的功效。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，使这些令人兴奋的技术更接近临床 中间神经元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.