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 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 5

Mice treated with GBP recover forelimb function after cervical SCI.

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Mice treated with GBP recover forelimb function after cervical SCI. (A) ...
(A) Experimental scheme. (B) Recovery of forelimb skilled locomotor function was measured using the horizontal ladder rung-walking test. Mean and SEM (mixed model with repeated measures using compound symmetry covariance structure and controlled on baseline values ***P < 0.001; vehicle n = 15 and GBP n = 15 mice). (C) Replication of the study shown in B. Mean and SEM (mixed model with repeated measures using compound symmetry covariance structure and controlled on baseline values, **P < 0.01; vehicle n = 10 and GBP n = 10 mice). (D) Photographs showing forelimb footprints used for intermediary toe spread measurements. Green circles indicate normal toe spread. (E) Quantification of D. Box and whiskers (minimum to maximum) (2-way ANOVA followed by Tukey’s post test **P < 0.001; NS, not significant; vehicle n = 10 and GBP n = 9 mice). (F) Coronal sections of the brain were stained using NeuN and mCherry antibodies. Scale bar: 200 μm. Transient activation of hM4Di in corticospinal neurons abrogates recovery of (G) forelimb skilled walking and (H) forelimb symmetry (cylinder test) in rearing after C5 SCI in mice receiving GBP. Scatter plot (2-way ANOVA followed by Bonferroni’s post test ***P < 0.001; NS, not significant; vehicle n = 14 and GBP n = 11 mice).