Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations.
Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations.
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DOI：
10.1016/j.cell.2018.06.005
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发表时间：
2018-07-26
期刊：
影响因子：
64.5
通讯作者：
He Z
中科院分区：
文献类型：
--
作者：
Chen B;Li Y;Yu B;Zhang Z;Brommer B;Williams PR;Liu Y;Hegarty SV;Zhou S;Zhu J;Guo H;Lu Y;Zhang Y;Gu X;He Z
许多人类脊髓损伤在解剖学上是不完整的，但表现为完全瘫痪。在这些情况下，为什么备用轴突不能调节功能恢复，目前尚不清楚。为了研究这一点，我们对交错双侧半横断的小鼠进行了小分子筛查，在这些小鼠中，腰椎脊髓失去了所有直接的脑源性神经支配，但休眠的继电器电路仍然存在。我们发现，KCC2激动剂恢复了步进能力，这可以通过选择性表达KCC2或超极化DREADD来模拟，在交错的脊髓损伤之间和周围的抑制性中间神经元中。从机制上讲，这些治疗方法将这种由损伤引起的功能失调的脊髓回路转变为功能状态，促进了脑源性命令向腰椎脊髓的传递。因此，我们的结果确定脊髓抑制性中间神经元是限制损伤后下行输入整合到继电回路的障碍，并提示KCC2激动剂是促进脊髓损伤后功能恢复的有希望的治疗方法。小分子降低脊髓抑制中间神经元的兴奋性增强对下行输入的反应性并促进脊髓损伤后的功能恢复
Many human spinal cord injuries are anatomically incomplete, but exhibit complete paralysis. It is unknown why spared axons fail to mediate functional recovery in these cases. To investigate this, we undertook a small-molecule screen 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. We discovered that a KCC2 agonist restored stepping ability, which could be mimicked by selective expression of KCC2, or hyperpolarizing DREADDs, in the inhibitory interneurons between and around the staggered spinal lesions. Mechanistically, these treatments transformed this injury-induced dysfunctional spinal circuit to a functional state, facilitating the relay of brain-derived commands towards the lumbar spinal cord. Thus, our results identify spinal inhibitory interneurons as a roadblock limiting the integration of descending inputs into relay circuits after injury, and suggest KCC2 agonists as promising treatments for promoting functional recovery after spinal cord injury. Reducing the excitability of spinal cord inhibitory interneurons with a small molecule enhances responsiveness to descending inputs and promotes functional recovery after spinal cord injury in mice
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影响因子：
5.3
作者：
Arvanian, Victor L.;Schnell, Lisa;Lou, Li;Golshani, Roozbeh;Hunanyan, Arsen;Ghosh, Arko;Pearse, Damien D.;Robinson, John K.;Schwab, Martin E.;Fawcett, James W.;Mendell, Lorne M.
通讯作者：
Mendell, Lorne M.
影响因子：
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影响因子：
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作者：
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通讯作者：
Houle, John D.
DOI：
10.1073/pnas.0906593106
发表时间：
2009-11-10
影响因子：
11.1
作者：
Guettier, Jean-Marc;Gautam, Dinesh;Wess, Juergen
通讯作者：
Wess, Juergen
影响因子：
82.9
作者：
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通讯作者：
Sofroniew, Michael V.