The Calcium Channel Subunit Alpha2delta2 Suppresses Axon Regeneration in the Adult CNS

Highlights

• Large-scale transcriptome comparison identifies a novel regulator of axon growth

• Alpha2delta2 functions as a developmental switch that limits axon growth

• Alpha2delta2 inhibits axon growth via calcium influx through Cav2 channels

• Systemic PGB administration induces axon regeneration in the adult CNS

Summary

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.