PT  - JOURNAL ARTICLE
AU  - Christopher N. Hansen
AU  - Lesley C. Fisher
AU  - Rochelle J. Deibert
AU  - Lyn B. Jakeman
AU  - Haoqian Zhang
AU  - Linda Noble-Haeusslein
AU  - Susan White
AU  - D. Michele Basso
TI  - Elevated MMP-9 in the Lumbar Cord Early after Thoracic Spinal Cord Injury Impedes Motor Relearning in Mice
AID  - 10.1523/JNEUROSCI.1576-13.2013
DP  - 2013 Aug 07
TA  - The Journal of Neuroscience
PG  - 13101--13111
VI  - 33
IP  - 32
4099  - http://www.jneurosci.org/content/33/32/13101.short
4100  - http://www.jneurosci.org/content/33/32/13101.full
SO  - J. Neurosci.2013 Aug 07; 33
AB  - 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.