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

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.

Repurposing cell growth-regulating compounds identifies kenpaullone which ameliorates pathologic pain via normalization of inhibitory neurotransmission

“…Regulation of Kcc2 gene expression by GSK3ß and its kinase target d-cat is a novel insight of our study. This concept will permit rational exploration of links between GSK3ßèd-cat and attenuated Kcc2/KCC2 gene expression and the resulting malfunction of inhibitory neurotransmission in several other relevant neurologic and psychiatric conditions such as Alzheimer's Disease and other neurodegenerative diseases, psychoses, traumatic brain/spinal cord injury, Rett Syndrome, Autism Spectrum Disorders, and epilepsy (Boulenguez et al, 2010;Chen et al, 2018;Ferando et al, 2016;Freund and Meskenaite, 1992;Huberfeld et al, 2007;Hyde et al, 2011;Kahle et al, 2014b;Tang et al, 2016;Tao et al, 2012). We selected KP because of its previously reported neuroprotective properties for spinal motoneurons, brainstem auditory relay neurons, and hypoxia-injured hippocampal neurons (Liu et al, 2016;Reinhardt et al, 2019;Skardelly et al, 2011;Teitz et al, 2018;Winkelmann et al, 2015;Yang et al, 2013).…”

Restoration of Direct Corticospinal Communication Across Sites of Spinal Injury

“…Spinal cord injury disrupts the exchange of information between the brain and distal cord, causing impairments in sensory, motor, and autonomic function. In cases of incomplete injury, severed axons often sprout spontaneously to form new connections with spared tracts, creating detour circuits that re-route information around the injury (1)(2)(3)(4)(5)(6). Recent work involving transplants of neural progenitor cells has also succeeded in creating novel relay circuits as host axons invade and innervate graft-derived neurons, which in turn extend lengthy axons that innervate neurons in the caudal spinal cord (7)(8)(9).…”

“…Recent work involving transplants of neural progenitor cells has also succeeded in creating novel relay circuits as host axons invade and innervate graft-derived neurons, which in turn extend lengthy axons that innervate neurons in the caudal spinal cord (7)(8)(9). These indirect circuits, both endogenous and graft-derived, have yielded some gains in motor function after injury (4,6,7,9,10). Recovery remains partial, however, even as various pharmacological, rehabilitation, and stimulation strategies have attempted to enhance their functional output (4,6).…”

“…These indirect circuits, both endogenous and graft-derived, have yielded some gains in motor function after injury (4,6,7,9,10). Recovery remains partial, however, even as various pharmacological, rehabilitation, and stimulation strategies have attempted to enhance their functional output (4,6). Fundamentally, in the face of supraspinal control systems that evolved to rely on direct connectivity between supraspinal nuclei and spinal neurons, there may be a limit to the ability of detour or relay circuits to replace lost function, particularly for tasks involving fine motor control.…”

Electroacupuncture at Governor Vessel improves neurobehavioral function via reduction of complexin1

“…SCI causes profound and persistent neurological deficits, many of which result from the interruption of axonal connectivity (Asboth et al, 2018). On the other hand, scar formation, a long-lasting inflammatory response and myelin debris prevent the axon regeneration after SCI (Chen et al, 2018;Ruschel&Bradke, 2018). Thus, the prevailing model posits the benefit of promoting axonal extension by blocking extrinsic inhibitors or enhancing intrinsic activators when synapse exhibits the highest potential for plasticity (Wang et al, 2011).…”