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， 受损的脊椎节段然而，这些患者中约有一半完全失去肌肉控制， 在受伤水平以下的感觉。一个重要但尚未得到充分研究的问题是， 在这些情况下不能介导功能恢复。人体研究的最新进展表明，硬膜外 刺激与康复训练相结合可以使一些慢性瘫痪的SCI患者， 恢复自主运动，强调了重新激活这种休眠的脊髓回路的可行性。然而，在这方面， 有限的功能恢复只发生在刺激时。因此，理解为什么这幸免 脊髓回路在SCI后功能失调，如何最好地重新激活它，应该提供关键的见解 开发新的SCI功能恢复策略。在交错双侧半脑切除的小鼠中， 其中腰椎脊髓被剥夺了所有直接的脑源性神经支配， 我们发现，用KCC 2激动剂或 KCC 2的过度表达能够恢复这些瘫痪小鼠的行走能力。我们发现， 推拿能够纠正脊髓中继区内的过度抑制，使这一迂回回路， 将脑源性命令传输到腰脊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 几个相关的问题：损伤诱导的KCC 2下调的机制是什么？ 脊髓损伤？为什么实现的功能恢复是部分的，以及如何进一步加强这种 功能恢复？在临床上更相关的情况下，这些回路修改治疗的效果是什么？ 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?