Chondroitinase <scp>ABC</scp> promotes compensatory sprouting of the intact corticospinal tract and recovery of forelimb function following unilateral pyramidotomy in adult mice

<jats:title>Abstract</jats:title><jats:p>Chondroitin sulphate proteoglycans (<jats:styled-content style="fixed-case">CSPG</jats:styled-content>s) are extracellular matrix molecules whose inhibitory activity is attenuated by the enzyme chondroitinase <jats:styled-content style="fixed-case">ABC</jats:styled-content> (<jats:styled-content style="fixed-case">C</jats:styled-content>h<jats:styled-content style="fixed-case">ABC</jats:styled-content>). Here we assess whether <jats:styled-content style="fixed-case">CSPG</jats:styled-content> degradation can promote compensatory sprouting of the intact corticospinal tract (<jats:styled-content style="fixed-case">CST</jats:styled-content>) following unilateral injury and restore function to the denervated forelimb. Adult <jats:styled-content style="fixed-case">C</jats:styled-content>57<jats:styled-content style="fixed-case">BL</jats:styled-content>/6 mice underwent unilateral pyramidotomy and treatment with either <jats:styled-content style="fixed-case">C</jats:styled-content>h<jats:styled-content style="fixed-case">ABC</jats:styled-content> 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, <jats:styled-content style="fixed-case">C</jats:styled-content>h<jats:styled-content style="fixed-case">ABC</jats:styled-content>‐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 <jats:styled-content style="fixed-case">CST</jats:styled-content>, with numerous axons observed crossing the midline in the brainstem and spinal cord and terminating in denervated grey matter. <jats:styled-content style="fixed-case">CST</jats:styled-content> fibres in the denervated side of the spinal cord following <jats:styled-content style="fixed-case">C</jats:styled-content>h<jats:styled-content style="fixed-case">ABC</jats:styled-content> treatment were closely associated with the synaptic marker v<jats:styled-content style="fixed-case">G</jats:styled-content>lut1. Immunohistochemical assessment of chondroitin‐4‐sulphate revealed that <jats:styled-content style="fixed-case">CSPG</jats:styled-content>s were heavily digested around lamina <jats:styled-content style="fixed-case">X</jats:styled-content>, alongside midline crossing axons and in grey matter regions where sprouting axons and reduced peri‐neuronal net staining was observed. Thus, we demonstrate that <jats:styled-content style="fixed-case">CSPG</jats:styled-content> degradation promotes midline crossing and reinnervation of denervated target regions by intact <jats:styled-content style="fixed-case">CST</jats:styled-content> axons and leads to restored function in the denervated forepaw. Enhancing compensatory sprouting using <jats:styled-content style="fixed-case">C</jats:styled-content>h<jats:styled-content style="fixed-case">ABC</jats:styled-content> provides a route to restore function that could be applied to disorders such as spinal cord injury and stroke.</jats:p>