PMID- 26224775
OWN - NLM
STAT- MEDLINE
DCOM- 20160617
LR  - 20211203
IS  - 1522-1598 (Electronic)
IS  - 0022-3077 (Print)
IS  - 0022-3077 (Linking)
VI  - 114
IP  - 3
DP  - 2015 Sep
TI  - Mammalian target of rapamycin is required for phrenic long-term facilitation 
      following severe but not moderate acute intermittent hypoxia.
PG  - 1784-91
LID - 10.1152/jn.00539.2015 [doi]
AB  - Phrenic long-term facilitation (pLTF) is a persistent increase in phrenic nerve 
      activity after acute intermittent hypoxia (AIH). Distinct cell-signaling cascades 
      give rise to pLTF depending on the severity of hypoxemia within hypoxic episodes. 
      Moderate AIH (mAIH; three 5-min episodes, PaO2  approximately 35-55 mmHG) elicits pLTF by a 
      serotonin (5-HT)-dependent mechanism that requires new synthesis of brain-derived 
      neurotrophic factor (BDNF), activation of its high-affinity receptor (TrkB), and 
      ERK MAPK signaling. In contrast, severe AIH (sAIH; three 5-min episodes, PaO2 
       approximately 25-30 mmHG) elicits pLTF by an adenosine-dependent mechanism that requires new 
      TrkB synthesis and Akt signaling. Although both mechanisms require spinal protein 
      synthesis, the newly synthesized proteins are distinct, as are the neurochemicals 
      inducing plasticity (serotonin vs. adenosine). In many forms of neuroplasticity, 
      new protein synthesis requires translational regulation via mammalian target of 
      rapamycin (mTOR) signaling. Since Akt regulates mTOR activity, we hypothesized 
      that mTOR activity is necessary for sAIH- but not mAIH-induced pLTF. Phrenic 
      nerve activity in anesthetized, paralyzed, and ventilated rats was recorded 
      before, during, and 60 min after mAIH or sAIH. Rats were pretreated with 
      intrathecal injections of 20% DMSO (vehicle controls) or rapamycin (0.1 mM, 12 
      mul), a selective mTOR complex 1 inhibitor. Consistent with our hypothesis, 
      rapamycin blocked sAIH- but not mAIH-induced pLTF. Thus spinal mTOR activity is 
      required for adenosine-dependent (sAIH) but not serotonin-dependent (mAIH) pLTF, 
      suggesting that distinct mechanisms regulate new protein synthesis in these forms 
      of spinal neuroplasticity.
CI  - Copyright (c) 2015 the American Physiological Society.
FAU - Dougherty, Brendan J
AU  - Dougherty BJ
AD  - Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, 
      Wisconsin; and.
FAU - Fields, Daryl P
AU  - Fields DP
AD  - Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, 
      Wisconsin; and Department of Physical Therapy, University of Florida, 
      Gainesville, Florida.
FAU - Mitchell, Gordon S
AU  - Mitchell GS
AD  - Department of Comparative Biosciences, University of Wisconsin-Madison, Madison, 
      Wisconsin; and Department of Physical Therapy, University of Florida, 
      Gainesville, Florida gsmitche@phhp.ufl.edu.
LA  - eng
GR  - T32 GM008692/GM/NIGMS NIH HHS/United States
GR  - HL69064/HL/NHLBI NIH HHS/United States
GR  - HL111598/HL/NHLBI NIH HHS/United States
GR  - R01 HL111598/HL/NHLBI NIH HHS/United States
GR  - R01 HL069064/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 - 20150729
PL  - United States
TA  - J Neurophysiol
JT  - Journal of neurophysiology
JID - 0375404
RN  - 0 (Multiprotein Complexes)
RN  - EC 2.7.11.1 (Mechanistic Target of Rapamycin Complex 1)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - K72T3FS567 (Adenosine)
SB  - IM
MH  - Adenosine/metabolism
MH  - Animals
MH  - Hypoxia/*metabolism/physiopathology
MH  - *Long-Term Potentiation
MH  - Male
MH  - Mechanistic Target of Rapamycin Complex 1
MH  - Multiprotein Complexes/*metabolism
MH  - Phrenic Nerve/*metabolism/physiology
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - TOR Serine-Threonine Kinases/*metabolism
PMC - PMC4571765
OTO - NOTNLM
OT  - hypoxia
OT  - long-term facilitation
OT  - mTOR
OT  - motor neuron
OT  - phrenic
OT  - plasticity
OT  - rapamycin
OT  - spinal
OT  - translational regulation
EDAT- 2015/08/01 06:00
MHDA- 2016/06/18 06:00
PMCR- 2016/09/01
CRDT- 2015/07/31 06:00
PHST- 2015/06/02 00:00 [received]
PHST- 2015/07/28 00:00 [accepted]
PHST- 2015/07/31 06:00 [entrez]
PHST- 2015/08/01 06:00 [pubmed]
PHST- 2016/06/18 06:00 [medline]
PHST- 2016/09/01 00:00 [pmc-release]
AID - jn.00539.2015 [pii]
AID - JN-00539-2015 [pii]
AID - 10.1152/jn.00539.2015 [doi]
PST - ppublish
SO  - J Neurophysiol. 2015 Sep;114(3):1784-91. doi: 10.1152/jn.00539.2015. Epub 2015 
      Jul 29.