Elevated MMP-9 in the lumbar cord early after thoracic spinal cord injury impedes motor relearning in mice.
Spinal cord injury results in distant pathology around putative locomotor networks that may jeopardize the recovery of locomotion. We previously showed that activated microglia and increased cytokine expression extend at least 10 segments below the injury to influence sensory function. Matrix metalloproteinase-9 (MMP-9) is a potent regulator of acute neuroinflammation. Whether MMP-9 is produced remote to the injury or influences locomotor plasticity remains unexamined. Therefore, we characterized the lumbar enlargement after a T9 spinal cord injury in C57BL/6 (wild-type [WT]) and MMP-9-null (knock-out [KO]) mice. Within 24 h, resident microglia displayed an activated phenotype alongside increased expression of progelatinase MMP-3 in WT mice. By 7 d, increases in active MMP-9 around lumbar vasculature and production of proinflammatory TNF-α were evident. Deletion of MMP-9 attenuated remote microglial activation and restored TNF-α expression to homeostatic levels. To determine whether MMP-9 impedes locomotor plasticity, we delivered lumbar-focused treadmill training in WT and KO mice during early (2-9 d) or late (35-42 d) phases of recovery. Robust behavioral improvements were observed by 7 d, when only trained KO mice stepped in the open field. Locomotor improvements were retained for 4 weeks as identified using state of the art mouse kinematics. Neither training nor MMP-9 depletion alone promoted recovery. The same intervention delivered late was ineffective, suggesting that lesion site sparing is insufficient to facilitate activity-based training and recovery. Our work suggests that by attenuating remote mechanisms of inflammation, acute treadmill training can harness endogenous spinal plasticity to promote robust recovery.
Neuroscience Graduate Studies Program, Center for Brain and Spinal Cord Repair, School of Health and Rehabilitation Sciences, Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio 43210, USA.
Christopher N
CN
Hansen
Lesley C
LC
Fisher
Rochelle J
RJ
Deibert
Lyn B
LB
Jakeman
Haoqian
H
Zhang
Linda
L
Noble-Haeusslein
Susan
S
White
D Michele
DM
Basso
D000818:Animals; D001696:Biomechanical Phenomena; D002135:Calcium-Binding Proteins; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D005080:Exercise Test; D008124:Locomotion / Q000502:physiology*; D008161:Lumbosacral Region; D020778:Matrix Metalloproteinase 2; D019278:Matrix Metalloproteinase 3; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008840:Microfilament Proteins; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D020127:Recovery of Function / Q000502:physiology*; D013116:Spinal Cord / Q000201:enzymology*; D013119:Spinal Cord Injuries / Q000473:pathology*; D018709:Statistics, Nonparametric; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
C491049:Aif1 protein, mouse; D002135:Calcium-Binding Proteins; D008840:Microfilament Proteins; D014409:Tumor Necrosis Factor-alpha; D019278:Matrix Metalloproteinase 3; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9