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

Carlos B. Mantilla; Sarah M. Greising; Jessica M. Stowe; Wen Zhi Zhan; Gary C. Sieck

doi:10.1016/j.expneurol.2014.05.027

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

Carlos B. Mantilla, Sarah M. Greising, Jessica M. Stowe, Wen Zhi Zhan, Gary C. Sieck

Kinesiology

Research output: Contribution to journal › Article › peer-review

43 Scopus citations

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 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.

Original language	English (US)
Pages (from-to)	190-195
Number of pages	6
Journal	Experimental Neurology
Volume	261
DOIs	https://doi.org/10.1016/j.expneurol.2014.05.027
State	Published - Nov 2014

Bibliographical note

Funding 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.

Keywords

Brain-derived neurotrophic factor
Diaphragm muscle
EMG
Spinal cord injury

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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 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.",

keywords = "Brain-derived neurotrophic factor, Diaphragm muscle, EMG, Spinal cord injury",

author = "Mantilla, {Carlos B.} and Greising, {Sarah M.} and Stowe, {Jessica M.} and Zhan, {Wen Zhi} and Sieck, {Gary C.}",

note = "Funding 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.",

year = "2014",

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doi = "10.1016/j.expneurol.2014.05.027",

language = "English (US)",

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AU - Mantilla, Carlos B.

AU - Greising, Sarah M.

AU - Stowe, Jessica M.

AU - Zhan, Wen Zhi

AU - Sieck, Gary C.

N1 - Funding 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.

PY - 2014/11

Y1 - 2014/11

N2 - 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.

AB - 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.

KW - Brain-derived neurotrophic factor

KW - Diaphragm muscle

KW - EMG

KW - Spinal cord injury

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ER -

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

Abstract

Bibliographical note

Keywords

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