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

Ying Wang; Wei Wu; Xiangbing Wu; Yan Sun; Yi P Zhang; Ling-Xiao Deng; Melissa Jane Walker; Wenrui Qu; Chen Chen; Nai-Kui Liu; Qi Han; Heqiao Dai; Lisa BE Shields; Christopher B Shields; Dale R Sengelaub; Kathryn J Jones; George M Smith; Xiao-Ming Xu

doi:10.7554/eLife.39016

eLife (Sep 2018)

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

Ying Wang,
Wei Wu,
Xiangbing Wu,
Yan Sun,
Yi P Zhang,
Ling-Xiao Deng,
Melissa Jane Walker,
Wenrui Qu,
Chen Chen,
Nai-Kui Liu,
Qi Han,
Heqiao Dai,
Lisa BE Shields,
Christopher B Shields,
Dale R Sengelaub,
Kathryn J Jones,
George M Smith,
Xiao-Ming Xu

Affiliations

Ying Wang: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States; Neural Tissue Engineering Research Institute, Mudanjiang College of Medicine, Mudanjiang, China
Wei Wu: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Xiangbing Wu: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Yan Sun: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States; Department of Anatomy, Histology and Embryology, School of Basic Medical Sciences, Fudan University, Shanghai, China
Yi P Zhang: Norton Neuroscience Institute, Norton Healthcare, Louisville, United States
Ling-Xiao Deng: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Melissa Jane Walker: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Wenrui Qu: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Chen Chen: ORCiD; Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States; Program in Medical Neuroscience, Paul and Carole Stark Neurosciences Research Institute, Indiana University School of Medicine, Indiana, United States
Nai-Kui Liu: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Qi Han: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Heqiao Dai: Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States
Lisa BE Shields: ORCiD; Norton Neuroscience Institute, Norton Healthcare, Louisville, United States
Christopher B Shields: Norton Neuroscience Institute, Norton Healthcare, Louisville, United States
Dale R Sengelaub: Program in Neuroscience, Department of Psychological and Brain Sciences, Indiana University, Bloomington, United States
Kathryn J Jones: Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, United States
George M Smith: Shriners Hospitals Pediatric Research Center, Lewis Katz School of Medicine, Temple University, Philadelphia, United States
Xiao-Ming Xu: ORCiD; Spinal Cord and Brain Injury Research Group, Stark Neurosciences Research Institute, Indiana University School of Medicine, Indianapolis, United States; Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, United States; Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, United States

DOI: https://doi.org/10.7554/eLife.39016
Journal volume & issue: Vol. 7

Abstract

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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 two 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.

Published in eLife

ISSN: 2050-084X (Online)
Publisher: eLife Sciences Publications Ltd
Country of publisher: United Kingdom
LCC subjects: Medicine; Science: Biology (General)
Website: https://elifesciences.org

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