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

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. [Display omitted] •A KCC2 agonist restores stepping ability in paralyzed mice with spinal cord injuries•KCC2 expression in inhibitory neurons leads to functional recovery•Restoration of inhibition in injured spinal cord leads to functional recovery Reducing the excitability of spinal cord inhibitory interneurons with a small molecule enhances the injured spinal cord’s responsiveness to descending inputs and promotes functional recovery after spinal cord injury in mice.