Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period

Mantilla, Carlos B.; Sieck, Gary C.

doi:10.1152/japplphysiol.01192.2007

Cited by 51 publications

(37 citation statements)

References 109 publications

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“…As motor neurons make contact with muscle fibers, the number of motor neurons is greatly reduced. The process of motor neuron elimination takes place between E12 and E14 for phrenic motor neurons-that specifically innervate the diaphragm, the major muscle of respiration-for example, in mice [10]. In most types of motor neurons, up to 50 % of motor neurons are lost by apoptosis at this time, possibly involving motor neurons activity and their functional connections.…”

Section: Development Of the Nmjmentioning

confidence: 99%

Mechanisms controlling neuromuscular junction stability

Bloch‐Gallego

2014

Cell. Mol. Life Sci.

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The neuromuscular junction (NMJ) is the synaptic connection between motor neurons and muscle fibers. It is involved in crucial processes such as body movements and breathing. Its proper development requires the guidance of motor axons toward their specific targets, the development of multi-innervated myofibers, and a selective synapse stabilization. It first consists of the removal of excessive motor axons on myofibers, going from multi-innervation to a single innervation of each myofiber. Whereas guidance cues of motor axons toward their specific muscular targets are well characterized, only few molecular and cellular cues have been reported as clues for selecting and stabilizing specific neuromuscular junctions. We will first provide a brief summary on NMJ development. We will then review molecular cues that are involved in NMJ stabilization, in both pre- and post-synaptic compartments, considering motor neurons and Schwann cells on the one hand, and muscle on the other hand. We will provide links with pathologies and highlight advances that can be brought both by basic research on NMJ development and clinical data resulting from the analyses of neurodegeneration of synaptic connections to obtain a better understanding of this process. The goal of this review is to highlight the findings toward understanding the roles of poly- or single-innervations and the underlying mechanisms of NMJ stabilization.

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Section: Development Of the Nmjmentioning

confidence: 99%

Mechanisms controlling neuromuscular junction stability

Bloch‐Gallego

2014

Cell. Mol. Life Sci.

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“…At E17, ATP evoked bursts of inspiratory activity; hence, ATP may contribute to the endogenous activation of fetal breathing movements, which are important for respiratory muscle and lung development (Mantilla and Sieck, 2008). However, a major challenge to understanding the physiological significance of P2R signaling for central respiratory control is defining the conditions that evoke ATP release.…”

Section: Physiological Significancementioning

confidence: 99%

Tripartite Purinergic Modulation of Central Respiratory Networks during Perinatal Development: The Influence of ATP, Ectonucleotidases, and ATP Metabolites

Huxtable¹,

Zwicker²,

Poon³

et al. 2009

J. Neurosci.

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ATP released during hypoxia from the ventrolateral medulla activates purinergic receptors (P2Rs) to attenuate the secondary hypoxic depression of breathing by a mechanism that likely involves a P2Y 1 R-mediated excitation of preBötzinger complex (preBötC) inspiratory rhythm-generating networks. In this study, we used rhythmically active in vitro preparations from embryonic and postnatal rats and ATP microinjection into the rostral ventral respiratory group (rVRG)/preBötC to reveal that these networks are sensitive to ATP when rhythm emerges at embryonic day 17 (E17). The peak frequency elicited by ATP at E19 and postnatally was the same (ϳ45 bursts/min), but relative sensitivity was threefold greater at E19, reflecting a lower baseline frequency (5.6 Ϯ 0.9 vs 19.0 Ϯ 1.3 bursts/min). Combining microinjection techniques with ATP biosensors revealed that ATP concentration in the rVRG/preBötC falls rapidly as a result of active processes and closely correlates with inspiratory frequency. A phosphate assay established that preBötC-containing tissue punches degrade ATP at rates that increase perinatally. Thus, the agonist profile [ATP/ADP/adenosine (ADO)] produced after ATP release in the rVRG/preBötC will change perinatally. Electrophysiology further established that the ATP metabolite ADP is excitatory and that, in fetal but not postnatal animals, ADO at A 1 receptors exerts a tonic depressive action on rhythm, whereas A 1 antagonists extend the excitatory action of ATP on inspiratory rhythm. These data demonstrate that ATP is a potent excitatory modulator of the rVRG/preBötC inspiratory network from the time it becomes active and that ATP actions are determined by a dynamic interaction between the actions of ATP at P2 receptors, ectonucleotidases that degrade ATP, and ATP metabolites on P2Y and P1 receptors.

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“…This coincides with increasing functional diversity of ventilatory and non-ventilatory behaviors. In early postnatal development, because of lung and chest wall compliance there is a need to recruit a greater fraction of the diaphragm motor unit pool to accomplish resting breathing (Mantilla & Sieck, 2008b). If the longer term effects of diaphragm muscle inactivity following spinal cord injury results in diaphragm muscle atrophy and weakness, recruitment of a greater fraction of the motor pool would be required to sustain ventilation.…”

Section: Diaphragm Motor Unit Recruitmentmentioning

confidence: 99%

Role of neurotrophins in recovery of phrenic motor function following spinal cord injury

Sieck

Mantilla

2009

Respiratory Physiology & Neurobiology

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Many individuals who sustain a cervical spinal cord injury are unable to maintain adequate ventilation due to diaphragm muscle paralysis. These patients become dependent on mechanical ventilators and this situation is associated with ongoing problems with pulmonary clearance, infections, and lung injury leading to significant morbidity and reduced life expectancy. Therefore, functional recovery of rhythmic phrenic activity and the ability to generate expulsive forces would dramatically affect the quality of life of patients with cervical spinal cord injury. Neurotrophins are very promising in that they have been shown to play an important role in modulating functional neuroplasticity. Specifically, brain-derived neurotrophic factor (BDNF) acting via the tropomyosin-related kinase receptor type B (TrkB) has been implicated in neuroplasticity following spinal cord injury. Our central hypothesis is that functional recovery of rhythmic phrenic activity after cervical spinal cord injury is enhanced by an increase in BDNF/TrkB signaling in phrenic motoneurons, providing a novel therapeutic target for patients.

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Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period

Abstract: Mantilla CB, Sieck GC. Key aspects of phrenic motoneuron and diaphragm muscle development during the perinatal period.

Cited by 51 publications

References 109 publications

Mechanisms controlling neuromuscular junction stability

Mechanisms controlling neuromuscular junction stability

Tripartite Purinergic Modulation of Central Respiratory Networks during Perinatal Development: The Influence of ATP, Ectonucleotidases, and ATP Metabolites

Role of neurotrophins in recovery of phrenic motor function following spinal cord injury

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