TrkB kinase activity is critical for recovery of respiratory function after cervical spinal cord hemisection

• Published in: Experimental neurology 2014-11, Vol.261, p.190-195
• Main Authors: Mantilla, Carlos B., Greising, Sarah M., Stowe, Jessica M., Zhan, Wen-Zhi, Sieck, Gary C.
• Format: Article
• Language: English
• Subjects: Analysis of Variance; Animals; Brain-derived neurotrophic factor; Cervical Cord; Diaphragm - physiopathology; Diaphragm muscle; Disease Models, Animal; Electromyography; EMG; Functional Laterality - physiology; Male; Mice; Mice, Transgenic; Mutation - genetics; Protein Kinase Inhibitors - pharmacology; Pyrazoles - pharmacology; Pyrimidines - pharmacology; Receptor, trkB - genetics; Receptor, trkB - metabolism; Recovery of Function - drug effects; Recovery of Function - physiology; Respiration Disorders - etiology; Spinal Cord Injuries - complications; Spinal Cord Injuries - pathology; Spinal cord injury; Time Factors
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2014.05.027

Neuroplasticity following spinal cord injury contributes to spontaneous recovery over time. Recent studies highlight the important role of brain-derived neurotrophic factor (BDNF) signaling via the high-affinity tropomyosin-related kinase (Trk) receptor subtype B (TrkB) in recovery of rhythmic diaphragm activity following unilateral spinal hemisection at C2 (C2SH). We hypothesized that TrkB kinase activity is necessary for spontaneous recovery of diaphragm activity post-C2SH. A chemical-genetic approach employing adult male TrkBF616A mice (n=49) was used to determine the impact of inhibiting TrkB kinase activity by the phosphoprotein phosphatase 1 inhibitor derivative 1NMPP1 on recovery of ipsilateral hemidiaphragm EMG activity. In mice, C2SH was localized primarily to white matter tracts comprising the lateral funiculus. The extent of damaged spinal cord (~27%) was similar regardless of the presence of functional recovery, consistent with spontaneous recovery reflecting neuroplasticity primarily of contralateral spared descending pathways to the phrenic motor pools. Ipsilateral hemidiaphragm EMG activity was verified as absent in all mice at 3days post-C2SH. By 2weeks after C2SH, ipsilateral hemidiaphragm EMG activity was present in 39% of vehicle-treated mice compared to 7% of 1NMPP1-treated mice (P=0.03). These data support the hypothesis that BDNF/TrkB signaling involving TrkB kinase activity plays a critical role in spontaneous recovery of diaphragm activity following cervical spinal cord injury. •Unilateral C2 spinal hemisection causes ipsilateral loss of diaphragm EMG activity.•Spontaneous recovery of diaphragm activity is evident 14days after C2 injury.•A chemical-genetic approach permits in vivo inhibition of TrkB kinase activity.•Inhibiting TrkB kinase activity blunts spontaneous recovery after C2 hemisection.•TrkB kinase activity is critical for recovery following spinal cord injury.