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 3. days post-C2SH. By 2. weeks 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.
Bibliographical noteFunding Information:
We thank Dr. David D. Ginty (Johns Hopkins University) who kindly provided the original breeder pair of TrkB F616A mice. We would also like to thank Ms. Yun-Hua Fang for her technical assistance with the performance of immunohistochemical studies. This work was supported by NIH grants HL096750 (CBM & GCS), HL105355 (SMG) and the Mayo Clinic . The authors declare no competing financial interests.
- Brain-derived neurotrophic factor
- Diaphragm muscle
- Spinal cord injury