TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury

Gabriel Martínez-Gálvez, Juan M. Zambrano, Juan C. Diaz Soto, Wen Zhi Zhan, Heather M. Gransee, Gary C Sieck, Carlos Bernardo Mantilla

Research output: Contribution to journalArticle

22 Scopus citations

Abstract

Unilateral cervical spinal cord hemisection at C2 (C2SH) interrupts descending bulbospinal inputs to phrenic motoneurons, paralyzing the diaphragm muscle. Recovery after C2SH is enhanced by brain derived neurotrophic factor (BDNF) signaling via the tropomyosin-related kinase subtype B (TrkB) receptor in phrenic motoneurons. The role for gene therapy using adeno-associated virus (AAV)-mediated delivery of TrkB to phrenic motoneurons is not known. The present study determined the therapeutic efficacy of intrapleural delivery of AAV7 encoding for full-length TrkB (AAV-TrkB) to phrenic motoneurons 3 days post-C2SH. Diaphragm EMG was recorded chronically in male rats (n=26) up to 21 days post-C2SH. Absent ipsilateral diaphragm EMG activity was verified 3 days post-C2SH. A greater proportion of animals displayed recovery of ipsilateral diaphragm EMG activity during eupnea by 14 and 21 days post-SH after AAV-TrkB (10/15) compared to AAV-GFP treatment (2/11; p=0.031). Diaphragm EMG amplitude increased over time post-C2SH (p2=0.82), with increased motoneuron NMDA expression evident in animals treated with AAV-TrkB and that displayed recovery after C2SH. Overall, gene therapy using intrapleural delivery of AAV-TrkB to phrenic motoneurons is sufficient to promote recovery of diaphragm activity, adding a novel potential intervention that can be administered after upper cervical spinal cord injury to improve impaired respiratory function.

Original languageEnglish (US)
Pages (from-to)31-40
Number of pages10
JournalExperimental Neurology
Volume276
DOIs
StatePublished - Feb 1 2016

Keywords

  • Diaphragm muscle
  • Glutamatergic
  • Neuroplasticity
  • Neurotransmitter
  • Neurotrophin
  • Phrenic motoneuron
  • Respiratory
  • Serotonergic
  • Spinal hemisection

ASJC Scopus subject areas

  • Neurology
  • Developmental Neuroscience

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  • Cite this

    Martínez-Gálvez, G., Zambrano, J. M., Diaz Soto, J. C., Zhan, W. Z., Gransee, H. M., Sieck, G. C., & Mantilla, C. B. (2016). TrkB gene therapy by adeno-associated virus enhances recovery after cervical spinal cord injury. Experimental Neurology, 276, 31-40. https://doi.org/10.1016/j.expneurol.2015.11.007