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Cell. 2018 Jul 26;174(3):521-535.e13. doi: 10.1016/j.cell.2018.06.005. Epub 2018 Jul 19.

Reactivation of Dormant Relay Pathways in Injured Spinal Cord by KCC2 Manipulations.

Author information

1
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA.
2
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001 Jiangsu, China.
3
Department of Neurosurgery, Brigham and Women's Hospital, 60 Fenwood Road., BTM 4th Floor, Boston, MA 02115, USA.
4
Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-innovation Center of Neuroregeneration, Nantong University, Nantong, 226001 Jiangsu, China. Electronic address: nervegu@ntu.edu.cn.
5
F.M. Kirby Neurobiology Center, Boston Children's Hospital, and Department of Neurology, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA. Electronic address: zhigang.he@childrens.harvard.edu.

Abstract

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.

KEYWORDS:

KCC2; excitability; excitation/inhibition balance; inhibitory neurons; propriospinal pathways; spinal cord injury

PMID:
30033363
PMCID:
PMC6063786
DOI:
10.1016/j.cell.2018.06.005
[Indexed for MEDLINE]
Free PMC Article

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