Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

Satriotomo, Irawan; Dale, Erica A.; Dahlberg, Jenny M; Mitchell, Gordon S.

doi:10.1016/j.expneurol.2012.05.020

Cited by 65 publications

(73 citation statements)

References 76 publications

(141 reference statements)

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“…In addition to these pathways, molecular mechanisms mediated by vascular endothelial growth factor (66), and Epo (64), have also recently been described, and both pathways interact with ERK and Akt signaling (63–66, 352). It remains to be seen whether these mechanisms are components of the Q or S Pathways, or if they represent entirely new molecular mechanisms that mediate LTF.…”

Section: Physiological and Molecular Responses To Episodic Hypoxic Exmentioning

confidence: 99%

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Pamenter

Powell

2016

Comprehensive Physiology

108

101

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Ventilatory responses to hypoxia vary widely depending on the pattern and length of hypoxic exposure. Acute, prolonged, or intermittent hypoxic episodes can increase or decrease breathing for seconds to years, both during the hypoxic stimulus, and also after its removal. These myriad effects are the result of a complicated web of molecular interactions that underlie plasticity in the respiratory control reflex circuits and ultimately control the physiology of breathing in hypoxia. Since the time domains of the physiological hypoxic ventilatory response (HVR) were identified, considerable research effort has gone toward elucidating the underlying molecular mechanisms that mediate these varied responses. This research has begun to describe complicated and plastic interactions in the relay circuits between the peripheral chemoreceptors and the ventilatory control circuits within the central nervous system. Intriguingly, many of these molecular pathways seem to share key components between the different time domains, suggesting that varied physiological HVRs are the result of specific modifications to overlapping pathways. This review highlights what has been discovered regarding the cell and molecular level control of the time domains of the HVR, and highlights key areas where further research is required. Understanding the molecular control of ventilation in hypoxia has important implications for basic physiology and is emerging as an important component of several clinical fields.

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Section: Physiological and Molecular Responses To Episodic Hypoxic Exmentioning

confidence: 99%

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Pamenter

Powell

2016

Comprehensive Physiology

108

101

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“…ERK expression is increased in the phrenic motor nucleus after repetitive AIH exposure Satriotomo et al, 2012), and increased expression may enhance phrenic motor plasticity ). Here we show that pERK expression in spared putative phrenic motor neurons in end-stage SOD1 G93A rats is increased (Fig.…”

Section: Mek/erk Signaling Is Required For Pltf In Sod1mentioning

confidence: 99%

“…ALS is a progressive neurodegenerative disease that results in phrenic motor neuron death, ultimately leading to ventilatory failure in ALS patients (Bourke et al, 2001;Lyall et al, 2001;Lechtzin et al, 2002;Iłzecka et al, 2003;Kiernan et al, 2011;Singh et al, 2011;Zinman and Cudkowicz, 2011). No effective treatment strategies are currently available that alter the course of ALS disease progression.…”

Section: Introductionmentioning

confidence: 99%

Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1^G93A Rats

et al. 2017

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Amyotrophic lateral sclerosis (ALS) is a degenerative motor neuron disease, causing muscle paralysis and death from respiratory failure. Effective means to preserve/restore ventilation are necessary to increase the quality and duration of life in ALS patients. At disease end-stage in a rat ALS model (SOD1 G93A), acute intermittent hypoxia (AIH) restores phrenic nerve activity to normal levels via enhanced phrenic long-term facilitation (pLTF). Mechanisms enhancing pLTF in end-stage SOD1 G93A rats are not known. Moderate AIH-induced pLTF is normally elicited via cellular mechanisms that require the following: G q -protein-coupled 5-HT 2 receptor activation, new BDNF synthesis, and MEK/ERK signaling (the Q pathway). In contrast, severe AIH elicits pLTF via a distinct mechanism that requires the following: G s -protein-coupled adenosine 2A receptor activation, new TrkB synthesis, and PI3K/Akt signaling (the S pathway). In endstage male SOD1G93A rats and wild-type littermates, we investigated relative Q versus S pathway contributions to enhanced pLTF via intrathecal (C4) delivery of small interfering RNAs targeting BDNF or TrkB mRNA, and MEK/ERK (U0126) or PI3 kinase/Akt (PI828) inhibitors. In anesthetized, paralyzed and ventilated rats, moderate AIH-induced pLTF was abolished by siBDNF and UO126, but not siTrkB or PI828, demonstrating that enhanced pLTF occurs via the Q pathway. Although phrenic motor neuron numbers were decreased in end-stage SOD1 G93A rats (ϳ30% survival; p Ͻ 0.001), BDNF and phosphorylated ERK expression were increased in spared phrenic motor neurons (p Ͻ 0.05), consistent with increased Q-pathway contributions to pLTF. Our results increase understanding of respiratory plasticity and its potential to preserve/restore breathing capacity in ALS.

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“…BDNF signaling in the region of the phrenic motoneuron pool is important in the response to respiratory perturbations such as exposure to intermittent hypoxia (Baker-Herman et al, 2004; Golder et al, 2008; Satriotomo et al, 2012). It is our view that targeting specific neuronal populations (e.g., phrenic motoneurons) is essential considering the potentially adverse effects associated with systemic BDNF administration.…”

Section: Bdnf/trkb Signaling In Phrenic Motoneuronsmentioning

confidence: 99%

Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons

Gill

Gransee

Sieck

et al. 2016

Respiratory Physiology & Neurobiology

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Cervical spinal cord injury (SCI) interrupts descending neural drive to phrenic motoneurons causing diaphragm muscle (DIAm) paralysis. Recent studies using a well-established model of SCI, unilateral spinal hemisection of the C2 segment of the cervical spinal cord (SH), provide novel information regarding the molecular and cellular mechanisms of functional recovery after SCI. Over time post-SH, gradual recovery of rhythmic ipsilateral DIAm activity occurs. Recovery of ipsilateral DIAm electromyogram (EMG) activity following SH is enhanced by increasing brain-derived neurotrophic factor (BDNF) in the region of the phrenic motoneuron pool. Delivery of exogenous BDNF either via intrathecal infusion or via mesenchymal stem cells engineered to release BDNF similarly enhance recovery. Conversely, recovery after SH is blunted by quenching endogenous BDNF with the fusion-protein TrkB-Fc in the region of the phrenic motoneuron pool or by selective inhibition of TrkB kinase activity using a chemical-genetic approach in TrkBF616A mice. Furthermore, the importance of BDNF signaling via TrkB receptors at phrenic motoneurons is highlighted by the blunting of recovery by siRNA-mediated downregulation of TrkB receptor expression in phrenic motoneurons and by the enhancement of recovery evident following virally-induced increases in TrkB expression specifically in phrenic motoneurons. BDNF/TrkB signaling regulates synaptic plasticity in various neuronal systems, including glutamatergic pathways. Glutamatergic neurotransmission constitutes the main inspiratory-related, excitatory drive to motoneurons, and following SH, spontaneous neuroplasticity is associated with increased expression of ionotropic N-methyl-D-aspartate (NMDA) receptors in phrenic motoneurons. Evidence for the role of BDNF/TrkB and glutamatergic signaling in recovery of DIAm activity following cervical SCI is reviewed.

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Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

Cited by 65 publications

References 76 publications

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1^G93A Rats

Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons

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Repetitive acute intermittent hypoxia increases expression of proteins associated with plasticity in the phrenic motor nucleus

Cited by 65 publications

References 76 publications

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Time Domains of the Hypoxic Ventilatory Response and Their Molecular Basis

Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1G93A Rats

Functional recovery after cervical spinal cord injury: Role of neurotrophin and glutamatergic signaling in phrenic motoneurons

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Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1^G93A Rats