期刊
CELL
卷 174, 期 3, 页码 521-+出版社
CELL PRESS
DOI: 10.1016/j.cell.2018.06.005
关键词
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资金
- National Major Project of Research and Development [2017YFA0104701]
- NINDS [R01NS096294]
- Craig Neilsen Foundation [384775, 296466]
- Paralyzed Veterans of America Research Foundation [PVA_R_0059]
- Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
- NIH [P30 HD018655, P30EY012196]
- EUNICE KENNEDY SHRIVER NATIONAL INSTITUTE OF CHILD HEALTH & HUMAN DEVELOPMENT [P30HD018655] Funding Source: NIH RePORTER
- NATIONAL EYE INSTITUTE [P30EY012196] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE [R01NS096294] Funding Source: NIH RePORTER
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 toward 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.
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