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

Elife. 2018 Sep 12;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 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.

Keywords: NT-3; dendritic morphology; lumbar motoneuron; mouse; neuroscience; plasticity; retrograde transport; spinal cord injury.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cells, Cultured
  • Dendrites / physiology
  • Dependovirus / genetics
  • Female
  • Male
  • Mice, Inbred C57BL
  • Motor Activity / physiology*
  • Motor Neurons / metabolism
  • Motor Neurons / physiology*
  • Neurotrophin 3 / genetics
  • Neurotrophin 3 / metabolism
  • Rats, Sprague-Dawley
  • Recovery of Function / physiology*
  • Spinal Cord / physiopathology*
  • Spinal Cord Injuries / genetics
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / physiopathology*
  • Synaptic Transmission / genetics
  • Synaptic Transmission / physiology
  • Thoracic Vertebrae

Substances

  • Neurotrophin 3