Combination of chondroitinase ABC and AAV-NT3 promotes neural plasticity at descending spinal pathways after thoracic contusion in rats

Abstract

Transmission through descending pathways to lumbar motoneurons, although important for voluntary walking in humans and rats, has not been fully understood at the cellular level in contusion models. Major descending pathways innervating lumbar motoneurons include those at corticospinal tract (CST) and ventrolateral funiculus (VLF). We examined transmission and plasticity at synaptic pathways from dorsal (d)CST and VLF to individual motoneurons located in ventral horn and interneurons located in dorsomedial gray matter at lumbar segments after thoracic chronic contusion in adult anesthetized rats. To accomplish this, we used intracellular electrophysiological recordings and performed acute focal spinal lesions during the recordings. We directly demonstrate that after thoracic T10 chronic contusion the disrupted dCST axons spontaneously form new synaptic contacts with individual motoneurons, extending around the contusion cavity, through spared ventrolateral white matter. These detour synaptic connections are very weak, and strengthening these connections in order to improve function may be a target for therapeutic interventions after spinal cord injury (SCI). We found that degradation of scar-related chondroitin sulfate proteoglycans with the enzyme chondroitinase ABC (ChABC) combined with adeno-associated viral (AAV) vector-mediated prolonged delivery of neurotrophin NT-3 (AAV-NT3) strengthened these spontaneously formed connections in contused spinal cord. Moreover, ChABC/AAV-NT3 treatment induced the appearance of additional detour synaptic pathways innervating dorsomedial interneurons. Improved transmission in ChABC/AAV-NT3-treated animals was associated with increased immunoreactivity of 5-HT-positive fibers in lumbar dorsal and ventral horns. Improved locomotor function assessed with automated CatWalk highlights the physiological significance of these novel connections.