Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery
- Indiana University School of Medicine, United States
- Norton Healthcare, United States
- Indiana University, United States
- Temple University, United States
Abstract
Retrogradely-transported neurotrophin signaling plays an important role in regulating neural circuit specificity. Here we investigated whether targeted delivery of neurotrophin-3 (NT-3) to lumbar motoneurons (MNs) caudal to a thoracic (T10) contusive spinal cord injury (SCI) could modulate dendritic patterning and synapse formation of the lumbar MNs. In vitro, Adeno-associated virus serotype 2 overexpressing NT-3 (AAV-NT-3) induced NT-3 expression and neurite outgrowth in cultured spinal cord neurons. In vivo, targeted delivery of AAV-NT-3 into transiently demyelinated adult mouse sciatic nerves led to the retrograde transportation of NT-3 to the lumbar MNs, significantly attenuating SCI-induced lumbar MN dendritic atrophy. NT-3 enhanced sprouting and synaptic formation of descending serotonergic, dopaminergic, and propriospinal axons on lumbar MNs, parallel to improved behavioral recovery. Thus, retrogradely transported NT-3 stimulated remodeling of lumbar neural circuitry and synaptic connectivity remote to a thoracic SCI, supporting a role for retrograde transport of NT-3 as a potential therapeutic strategy for SCI.
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All data generated or analyzed during this study are included in the manuscript and supporting files.
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Funding
National Institutes of Health (R01 NS103481)
- Xiao-Ming Xu
U.S. Department of Veterans Affairs (I01 RX002356-01)
- Xiao-Ming Xu
Craig H. Neilsen Foundation (296749)
- Xiao-Ming Xu
Indiana State Department of Health (19919)
- Xiao-Ming Xu
National Institutes of Health (R01 NS100531)
- Xiao-Ming Xu
U.S. Department of Veterans Affairs (I01 BX003705-01A1)
- Xiao-Ming Xu
Science Fund Project of Natural Science Foundation of China (81870977)
- Ying Wang
National Institutes of Health (NS059622)
- Xiao-Ming Xu
U.S. Department of Defense (CDMRP W81XWH-12-1-0562)
- Xiao-Ming Xu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All surgical interventions, treatments, and postoperative animal care were performed following the Guide for the Care and Use of Laboratory Animals (National Research Council) and the Guidelines set forth by the Institutional Animal Care and Use Committee of the Indiana University School of Medicine.
Copyright
© 2018, Wang et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery
eLife 7:e39016.
https://doi.org/10.7554/eLife.39016
