Hypertrophic scarring and poor intrinsic axon growth capacity constitute major obstacles for spinal cord repair. These processes are tightly regulated by microtubule dynamics. We found that moderate microtubule stabilization decreased scar formation after spinal cord injury (SCI) in rodents via various cellular mechanisms, including dampening of TFG-β signalling. It prevented the accumulation of chondroitin sulfate proteoglycans (CSPGs) and rendered the lesion site permissive for axon regeneration of growth competent sensory neurons. Additionally, microtubule stabilization promoted growth of CNS axons of the Raphe-spinal tract and led to functional improvement. Thus, microtubule stabilization reduces fibrotic scarring and enhances the capacity of axons to grow. Manipulation of microtubules may offer the basis for a multi-targeted therapy after SCI.

Injuries to the adult CNS often result in permanent disabilities because neurons lose the ability to regenerate their axon during development. Here, whole transcriptome sequencing and bioinformatics analysis followed by gain- and loss-of-function experiments identified Cacna2d2, the gene encoding the Alpha2delta2 subunit of voltage-gated calcium channels (VGCCs), as a developmental switch that limits axon growth and regeneration. Cacna2d2 gene deletion or silencing promoted axon growth in vitro. In vivo, Alpha2delta2 pharmacological blockade through Pregabalin (PGB) administration enhanced axon regeneration in adult mice after spinal cord injury (SCI). As PGB is already an established treatment for a wide range of neurological disorders, our findings suggest that targeting Alpha2delta2 may be a novel treatment strategy to promote structural plasticity and regeneration following CNS trauma.

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Highlights d Elevated actin turnover is essential for regenerative growth d ADF/cofilin activity increases during conditioning-mediated regeneration d ADF/cofilin is necessary and sufficient for axon regeneration d The severing activity of ADF/cofilin is critical for axon regeneration