Axon regeneration failure causes neurological deficits and long-term disability after spinal cord injury (SCI). Here, we found that the α2δ2 subunit of voltage-gated calcium channels negatively regulates axon growth and regeneration of corticospinal neurons, the cells that originate the corticospinal tract. Increased α2δ2 expression in corticospinal neurons contributed to loss of corticospinal regrowth ability during postnatal development and after SCI. In contrast, α2δ2 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 α2δ2 with a clinically relevant treatment strategy aids repair of motor circuits after SCI.

中文翻译：

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Gabapentinoid治疗促进鼠脊髓损伤后皮质脊髓可塑性和再生

轴突再生失败会导致脊髓损伤（SCI）后神经功能缺损和长期残疾。在这里，我们发现电压门控性钙通道的α2δ2亚基负调控了皮质脊髓神经元（起源于皮质脊髓束的细胞）的轴突生长和再生。皮质脊髓神经元中增加的α2δ2表达导致出生后发育过程中和脊髓损伤后皮质脊髓再生能力的丧失。相反，通过加巴喷丁给药的α2δ2药理学阻断促进了成年期皮质脊髓结构的可塑性和再生。使用结合体内电生理记录的光遗传学策略，我们证明了再生皮质脊髓轴突功能整合到脊髓电路。加巴喷丁的小鼠在颈脊髓损伤后恢复了上肢功能。重要的是，这种恢复依赖于皮质脊髓通路的重组，因为受损的皮质脊髓神经元的化学遗传沉默暂时消除了恢复。因此，以临床相关的治疗策略靶向α2δ2有助于修复SCI后的运动回路。