title: TrkB kinase activity is critical for recovery of respiratory function after cervical spinal cord hemisection.
abstract: 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 TrkB(F616A) 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.
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. Electronic address: mantilla.carlos@mayo.edu.
authors.forename: Carlos B
authors.initials: CB
authors.lastname: Mantilla
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Greising
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Stowe
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Wen-Zhi
authors.initials: WZ
authors.lastname: Zhan
authors.affiliation: Department of Physiology and Biomedical Engineering, Mayo Clinic College of Medicine, Rochester, MN 55905, USA; Department of Anesthesiology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
authors.forename: Gary C
authors.initials: GC
authors.lastname: Sieck
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D066193:Cervical Cord; D003964:Diaphragm / Q000503:physiopathology; D004195:Disease Models, Animal; D004576:Electromyography; D007839:Functional Laterality / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020813:Receptor, trkB / Q000235:genetics / Q000378:metabolism*; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology*; D012120:Respiration Disorders / Q000209:etiology*; D013119:Spinal Cord Injuries / Q000150:complications* / Q000473:pathology; D013997:Time Factors
chemical_list: C582212:1NMPP1 compound; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; D020813:Receptor, trkB
keywords: Brain-derived neurotrophic factor; Diaphragm muscle; EMG; Spinal cord injury