PMID- 23583688
OWN - NLM
STAT- MEDLINE
DCOM- 20131126
LR  - 20220311
IS  - 1090-2430 (Electronic)
IS  - 0014-4886 (Print)
IS  - 0014-4886 (Linking)
VI  - 247
DP  - 2013 Sep
TI  - Motoneuron BDNF/TrkB signaling enhances functional recovery after cervical spinal 
      cord injury.
PG  - 101-9
LID - S0014-4886(13)00122-2 [pii]
LID - 10.1016/j.expneurol.2013.04.002 [doi]
AB  - A C2 cervical spinal cord hemisection (SH) interrupts descending 
      inspiratory-related drive to phrenic motoneurons located between C3 and C5 in 
      rats, paralyzing the ipsilateral hemidiaphragm muscle. There is gradual recovery 
      of rhythmic diaphragm muscle activity ipsilateral to cervical spinal cord injury 
      over time, consistent with neuroplasticity and strengthening of spared, 
      contralateral descending premotor input to phrenic motoneurons. Brain-derived 
      neurotrophic factor (BDNF) signaling through the tropomyosin related kinase 
      receptor subtype B (TrkB) plays an important role in neuroplasticity following 
      spinal cord injury. We hypothesized that 1) increasing BDNF/TrkB signaling at the 
      level of the phrenic motoneuron pool by intrathecal BDNF delivery enhances 
      functional recovery of rhythmic diaphragm activity after SH, and 2) inhibiting 
      BDNF/TrkB signaling by quenching endogenous neurotrophins with the soluble fusion 
      protein TrkB-Fc or by knocking down TrkB receptor expression in phrenic 
      motoneurons using intrapleurally-delivered siRNA impairs functional recovery 
      after SH. Diaphragm EMG electrodes were implanted bilaterally to verify complete 
      hemisection at the time of SH and 3days post-SH. After SH surgery in adult rats, 
      an intrathecal catheter was placed at C4 to chronically infuse BDNF or TrkB-Fc 
      using an implanted mini-osmotic pump. At 14days post-SH, all intrathecal BDNF 
      treated rats (n=9) displayed recovery of ipsilateral hemidiaphragm EMG activity, 
      compared to 3 out of 8 untreated SH rats (p<0.01). During eupnea, BDNF treated 
      rats exhibited 76+/-17% of pre-SH root mean squared EMG vs. only 5+/-3% in untreated 
      SH rats (p<0.01). In contrast, quenching endogenous BDNF with intrathecal TrkB-Fc 
      treatment completely prevented functional recovery up to 14days post-SH (n=7). 
      Immunoreactivity of the transcription factor cAMP response element-binding 
      protein (CREB), a downstream effector of TrkB signaling, increased in phrenic 
      motoneurons following BDNF treatment (n=6) compared to artificial cerebrospinal 
      fluid treatment (n=6; p<0.001). Intrapleural injections of non-sense or TrkB 
      siRNA were administered after SH to specifically target phrenic motoneurons. At 
      14days post-SH, none out of 9 TrkB siRNA treated rats displayed functional 
      recovery compared to 5 out of 9 non-sense siRNA treated rats. These results 
      indicate that BDNF/TrkB signaling in phrenic motoneuron pool plays a critical 
      role in functional recovery after cervical spinal cord injury.
CI  - Copyright (c) 2013 Elsevier Inc. All rights reserved.
FAU - Mantilla, Carlos B
AU  - Mantilla CB
AD  - Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN 
      55905, USA. mantilla.carlos@mayo.edu
FAU - Gransee, Heather M
AU  - Gransee HM
FAU - Zhan, Wen-Zhi
AU  - Zhan WZ
FAU - Sieck, Gary C
AU  - Sieck GC
LA  - eng
GR  - R01 HL096750/HL/NHLBI NIH HHS/United States
GR  - T32 HL105355/HL/NHLBI NIH HHS/United States
GR  - R01-HL096750/HL/NHLBI NIH HHS/United States
GR  - T32-HL105355/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20130410
PL  - United States
TA  - Exp Neurol
JT  - Experimental neurology
JID - 0370712
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (RNA, Small Interfering)
RN  - EC 2.3.1.48 (CREB-Binding Protein)
RN  - EC 2.7.10.1 (Receptor, trkB)
SB  - IM
MH  - Analysis of Variance
MH  - Animals
MH  - Brain-Derived Neurotrophic Factor/*metabolism/therapeutic use
MH  - CREB-Binding Protein/metabolism
MH  - Disease Models, Animal
MH  - Electromyography
MH  - Functional Laterality/drug effects/physiology
MH  - Gene Expression Regulation/drug effects
MH  - Male
MH  - Motor Neurons/drug effects/*metabolism
MH  - Muscle, Skeletal/physiopathology
MH  - RNA, Small Interfering/administration & dosage
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, trkB/*metabolism/therapeutic use
MH  - Recovery of Function/drug effects/*physiology
MH  - Signal Transduction/drug effects/*physiology
MH  - Spinal Cord Injuries/*drug therapy/pathology/physiopathology
MH  - Time Factors
PMC - PMC3742616
MID - NIHMS466892
OTO - NOTNLM
OT  - CREB
OT  - Diaphragm muscle
OT  - Neuroplasticity
OT  - Neurotrophin
OT  - Phrenic motoneuron
OT  - Respiration
OT  - Respiratory
OT  - Spinal hemisection
OT  - TrkB-Fc
OT  - siRNA
EDAT- 2013/04/16 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/09/01
CRDT- 2013/04/16 06:00
PHST- 2013/02/22 00:00 [received]
PHST- 2013/04/02 00:00 [revised]
PHST- 2013/04/03 00:00 [accepted]
PHST- 2013/04/16 06:00 [entrez]
PHST- 2013/04/16 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/09/01 00:00 [pmc-release]
AID - S0014-4886(13)00122-2 [pii]
AID - 10.1016/j.expneurol.2013.04.002 [doi]
PST - ppublish
SO  - Exp Neurol. 2013 Sep;247:101-9. doi: 10.1016/j.expneurol.2013.04.002. Epub 2013 
      Apr 10.