Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury

摘要

Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the alpha 2 delta 2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased alpha 2 delta 2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, alpha 2 delta 2 pharmacological blockade through gabapentin administration promoted corticospinal structural plasticity and regeneration in adulthood. Using an optogenetic strategy combined with in vivo electrophysiological recording, we demonstrated that regenerating corticospinal axons functionally integrate into spinal circuits. Mice administered gabapentin recovered upper extremity function after cervical SCI. Importantly, such recovery relies on reorganization of the corticospinal pathway, as chemogenetic silencing of injured corticospinal neurons transiently abrogated recovery. Thus, targeting alpha 2 delta 2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.