Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury
Wenjing Sun, … , Juan Peng, Andrea Tedeschi
Wenjing Sun, … , Juan Peng, Andrea Tedeschi
Published January 2, 2020; First published December 3, 2019
Citation Information: J Clin Invest. 2020;130(1):345-358. https://doi.org/10.1172/JCI130391.
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Research Article Neuroscience

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

Abstract

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.

Authors

Wenjing Sun, Molly J.E. Larson, Conrad M. Kiyoshi, Alexander J. Annett, William A. Stalker, Juan Peng, Andrea Tedeschi

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Figure 3

α2δ2 pharmacological blockade promotes corticospinal sprouting in adulthood.

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α2δ2 pharmacological blockade promotes corticospinal sprouting in adulth...
(A) Experimental scheme of B. (B) Representative fluorescence images of C7 spinal cord sections from adult mice with unilateral PTX performed at 8 weeks of age. PKCγ staining is shown to confirm lesion completeness. The arrows indicate sprouting corticospinal axons (bottom panels). Scale bar: 500 μm. D, dorsal; V, ventral. (C) Quantification of B. Mean and SEM (unpaired 2-tailed Student’s t test *P < 0.05; vehicle n = 6 and GBP n = 6 mice). (D) Coronal sections of the medullary pyramid showing BDA-labeled corticospinal axons. Scale bar: 50 μm. (E) Quantification of D (unpaired 2-tailed Student’s t test NS, not significant; vehicle n = 6 and GBP n = 6 mice). (F) α2δ2 expression in corticospinal neurons 4 weeks after PTX. Sagittal sections of the mouse brain (left and right hemispheres) were immunostained with α2δ2 antibody. Mean and SEM (1-way ANOVA followed by Dunnett post test *P < 0.05; **P < 0.01; vehicle n = 6 and GBP n = 6 mice, 349–396 neurons per condition). (G) Representative fluorescence images of C7 spinal cord sections from mice with unilateral PTX performed in adulthood treated with GBP. The arrows indicate excitatory synaptic puncta along sprouting corticospinal axons. Inset, 3D reconstruction of the region in the main panel indicated by the yellow arrow. Scale bar: 100 μm.