1. Neuroscience
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Remodeling of lumbar motor circuitry remote to a thoracic spinal cord injury promotes locomotor recovery

  1. Ying Wang
  2. Wei Wu
  3. Xiangbing Wu
  4. Yan Sun
  5. Yi P Zhang
  6. Ling-Xiao Deng
  7. Melissa Jane Walker
  8. Wenrui Qu
  9. Chen Chen
  10. Nai-Kui Liu
  11. Qi Han
  12. Heqiao Dai
  13. Lisa BE Shields
  14. Christopher B Shields
  15. Dale R Sengelaub
  16. Kathryn J Jones
  17. George M Smith
  18. Xiao-Ming Xu  Is a corresponding author
  1. Indiana University School of Medicine, United States
  2. Norton Healthcare, United States
  3. Indiana University, United States
  4. Temple University, United States
Research Article
  • Cited 22
  • Views 1,829
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Cite this article as: eLife 2018;7:e39016 doi: 10.7554/eLife.39016

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.

Data availability

All data generated or analyzed during this study are included in the manuscript and supporting files.

Article and author information

Author details

  1. Ying Wang

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Wei Wu

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Xiangbing Wu

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Yan Sun

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Yi P Zhang

    Norton Neuroscience Institute, Norton Healthcare, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Ling-Xiao Deng

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Melissa Jane Walker

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Wenrui Qu

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Chen Chen

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Nai-Kui Liu

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Qi Han

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Heqiao Dai

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  13. Lisa BE Shields

    Norton Neuroscience Institute, Norton Healthcare, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-1526-4063
  14. Christopher B Shields

    Norton Neuroscience Institute, Norton Healthcare, Louisville, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Dale R Sengelaub

    Program in Neuroscience, Indiana University, Bloomington, United States
    Competing interests
    The authors declare that no competing interests exist.
  16. Kathryn J Jones

    Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, United States
    Competing interests
    The authors declare that no competing interests exist.
  17. George M Smith

    Shriners Hospitals Pediatric Research Center, School of Medicine, Temple University, Philadelphia, United States
    Competing interests
    The authors declare that no competing interests exist.
  18. Xiao-Ming Xu

    Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States
    For correspondence
    xu26@iupui.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7229-0081

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.

Reviewing Editor

  1. Moses V Chao, New York University Langone Medical Center, United States

Publication history

  1. Received: June 7, 2018
  2. Accepted: September 9, 2018
  3. Accepted Manuscript published: September 12, 2018 (version 1)
  4. Version of Record published: October 3, 2018 (version 2)

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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