KCC2 and Spinal Cord Injury

摘要/项目摘要 大多数人类脊髓损伤(SCI)在解剖学上是不完整的，备用的轴突横跨 受损的脊椎节段。然而，这些患者中约有一半完全失去了肌肉控制和 伤情水平以下的感觉。一个重要但研究不足的问题是，为什么这样的联系没有被 在这些病例中未能调解功能恢复。人类研究的最新进展表明，硬膜外麻醉 刺激结合康复训练使一些慢性瘫痪的脊髓损伤患者 恢复自主运动，突出了重新激活这种休眠的脊髓回路的可行性。然而， 只有当刺激开启时，有限的功能恢复才会发生。因此，理解为什么这会幸免于 脊髓损伤后脊髓回路功能障碍，以及如何最好地重新激活它，应该提供关键的见解 为脊髓损伤开发新的功能恢复策略。在双侧半横断交错的小鼠中， 腰髓被剥夺了所有直接的脑源性神经支配，但休眠的中继电路 保留在受损节段之间，我们发现用KCC2激动剂或 KCC2的过度表达，能够恢复这些瘫痪小鼠的行走能力。我们展示了这样的情况 手法能够纠正脊髓中继区内的过度抑制，允许这一迂回电路 将大脑派生的命令传输到腰髓中的后肢运动命令中心， 导致功能恢复。有了这些令人兴奋的初步结果，这项拟议的研究将解决 几个相关问题：损伤诱导KCC2下调的机制是什么？ 脊髓受伤？为什么已实现的功能恢复是部分的，如何进一步提高这种能力 功能恢复？这些电路改变疗法对临床上更相关的患者有什么影响？ 损伤模型，即严重挫伤模型？

Abstract/Project Summary Most human spinal cord injuries (SCIs) are anatomically incomplete, with spared axons spanning the damaged spinal segments. However, about a half of these patients have a total loss of muscle control and sensation below the injury level. An important but under-studied question is why such spared connections fail to mediate functional recovery in these cases. Recent advances in human studies show that epidural stimulation combined with rehabilitative training allows some chronically paralyzed patients with SCI to regain voluntary movement, highlights the feasibility of reactivating such dormant spinal circuitry. However, the limited functional recovery only occurs when the stimulation is on. Thus, understanding why this spared spinal circuitry is dysfunctional after SCI, and how it can best be reactivated, should provide key insights into developing novel functional restoration strategies for SCI. In mice with staggered bilateral hemisections, in which the lumbar spinal cord is deprived of all direct brain-derived innervation but dormant relay circuits remain between the damaged segments, we discovered that systematic treatment with a KCC2 agonist, or over-expression of KCC2, is able to restore stepping ability in these paralyzed mice. We showed that such manipulations are able to correct over-inhibition within the spinal relay zone, allowing this detour circuit to transmit the brain-derived commands to the hindlimb motor command center in the lumbar spinal cord, leading to functional recovery. With these exciting preliminary results, this proposed study will address several related questions: what is the mechanism underlying injury-induced KCC2 down-regulation in injured spinal cord? Why the achieved functional recovery is partial and how to further enhance such functional recovery? What are the effects of these circuit-modifying treatments in more clinically relevant injury models, namely severe contusion models?