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.
View: Text | PDF
Research Article Neuroscience Article has an altmetric score of 220

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

×

Figure 2

α2δ2 inhibits axon growth of cortical neurons.

Options: View larger image (or click on image) Download as PowerPoint
α2δ2 inhibits axon growth of cortical neurons. (A) Experimental scheme o...
(A) Experimental scheme of B. (B) Representative fluorescence images of C7 spinal cord sections from mice with sham operation or unilateral PTX performed at P10. PKCγ staining is shown to confirm lesion completeness. Scale bar: 500 μm. D, dorsal; V, ventral. (C) Quantification of B. Mean and SEM (unpaired 2-tailed Student’s t test **P < 0.01; sham n = 6 and PTX n = 5 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; sham n = 6 and PTX n = 5 mice). (F) Representative fluorescence images of corticospinal neurons 32 days after sham or PTX at P10. Sagittal sections of the mouse brain (right hemisphere) were immunostained with α2δ2 antibody. Scale bar: 25 μm. (G) Quantification of F (unpaired 2-tailed Student’s t test **P < 0.01; sham n = 6 and PTX n = 5 mice; 278–369 neurons per condition). (H) Representative fluorescence images of C7 spinal cord sections from mice with unilateral PTX performed at P10. 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. (I) Immunoblot showing α2δ2 expression in E17.5 cortical neurons cultured for 48 hours after electroporation with GFP plus either control (CTR) or Cacna2d2-expressing plasmids. Tuj1 is shown as a loading control (n = 3 independent replicates per condition). (J) Representative fluorescence images of E17.5 cortical neurons cultured for 48 hours after electroporation with GFP plus either CTR or Cacna2d2-expressing plasmids. DIV, day in vitro. Scale bar: 100 μm. (K) Quantification of J. Mean and SEM (unpaired 2-tailed Student’s t test ***P < 0.001; triplicate experiments; 134–144 neurons per condition). (L) Representative fluorescence images of E17.5 cortical neurons cultured for 48 hours in the presence of either vehicle (0.9% saline) or 250 μM GBP. Scale bar: 100 μm. (M) Quantification of L. Mean and SEM (unpaired 2-tailed Student’s t test ***P < 0.001; 4 independent experiments; 163–165 neurons per condition).