Chondroitinase ABC promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice.
Chondroitin sulphate proteoglycans (CSPGs) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase ABC (ChABC). Here we assess whether CSPG degradation can promote compensatory sprouting of the intact corticospinal tract (CST) following unilateral injury and restore function to the denervated forelimb. Adult C57BL/6 mice underwent unilateral pyramidotomy and treatment with either ChABC or a vehicle control. Significant impairments in forepaw symmetry were observed following pyramidotomy, with injured mice preferentially using their intact paw during spontaneous vertical exploration of a cylinder. No recovery on this task was observed in vehicle-treated mice. However, ChABC-treated mice showed a marked recovery of function, with forelimb symmetry fully restored by 5 weeks post-injury. Functional recovery was associated with robust sprouting of the uninjured CST, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. CST fibres in the denervated side of the spinal cord following ChABC treatment were closely associated with the synaptic marker vGlut1. Immunohistochemical assessment of chondroitin-4-sulphate revealed that CSPGs were heavily digested around lamina X, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri-neuronal net staining was observed. Thus, we demonstrate that CSPG degradation promotes midline crossing and reinnervation of denervated target regions by intact CST axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using ChABC provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke.
Regeneration Group, King's College London, Wolfson Centre for Age-Related Diseases, Hodgkin Building, Guy's Campus, London Bridge, London, SE1 IUL, UK.
Michelle L
ML
Starkey
Katalin
K
Bartus
Andrew W
AW
Barritt
Elizabeth J
EJ
Bradbury
D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology; D019765:Chondroitin ABC Lyase / Q000378:metabolism / Q000494:pharmacology* / Q000627:therapeutic use; D011508:Chondroitin Sulfate Proteoglycans / Q000378:metabolism; D002809:Chondroitin Sulfates / Q000378:metabolism; D003714:Denervation; D005552:Forelimb / Q000294:innervation*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011712:Pyramidal Tracts / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery; D013119:Spinal Cord Injuries / Q000188:drug therapy; D058630:Spinal Cord Regeneration / Q000187:drug effects
D011508:Chondroitin Sulfate Proteoglycans; D002809:Chondroitin Sulfates; D019765:Chondroitin ABC Lyase