The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability

Viviana Pérez, Francisca Bermedo-Garcia, Diego Zelada, Felipe A. Court, Miguel Ángel Pérez, Marco Fuenzalida, Johanna Ábrigo, Claudio Cabello-Verrugio, Guillermo Moya-Alvarado, Juan Carlos Tapia, Vicente Valenzuela, Claudio Hetz, Francisca C. Bronfman, Juan Pablo Henríquez

Resultado de la investigación: Article

Resumen

The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

Idioma originalEnglish
Número de páginas1
PublicaciónActa neuropathologica communications
Volumen7
N.º1
DOI
EstadoPublished - 12 sep 2019

Huella dactilar

Nerve Growth Factor Receptors
Synaptic Vesicles
Synapses
Neuromuscular Junction
Muscles
Confocal Microscopy
Pharmacology
Peripheral Nerve Injuries
Schwann Cells
Skeletal Muscle Fibers
Presynaptic Terminals
Electromyography
Motor Neurons
Therapeutic Uses
Acetylcholinesterase
Electron Microscopy
Communication

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Clinical Neurology
  • Cellular and Molecular Neuroscience

Citar esto

Pérez, Viviana ; Bermedo-Garcia, Francisca ; Zelada, Diego ; Court, Felipe A. ; Pérez, Miguel Ángel ; Fuenzalida, Marco ; Ábrigo, Johanna ; Cabello-Verrugio, Claudio ; Moya-Alvarado, Guillermo ; Tapia, Juan Carlos ; Valenzuela, Vicente ; Hetz, Claudio ; Bronfman, Francisca C. ; Henríquez, Juan Pablo. / The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability. En: Acta neuropathologica communications. 2019 ; Vol. 7, N.º 1.
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title = "The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability",
abstract = "The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.",
keywords = "Motor neuron, Neuromuscular junction, Neurotrophin, p75NTR, Synaptic vesicles",
author = "Viviana P{\'e}rez and Francisca Bermedo-Garcia and Diego Zelada and Court, {Felipe A.} and P{\'e}rez, {Miguel {\'A}ngel} and Marco Fuenzalida and Johanna {\'A}brigo and Claudio Cabello-Verrugio and Guillermo Moya-Alvarado and Tapia, {Juan Carlos} and Vicente Valenzuela and Claudio Hetz and Bronfman, {Francisca C.} and Henr{\'i}quez, {Juan Pablo}",
year = "2019",
month = "9",
day = "12",
doi = "10.1186/s40478-019-0802-7",
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Pérez, V, Bermedo-Garcia, F, Zelada, D, Court, FA, Pérez, MÁ, Fuenzalida, M, Ábrigo, J, Cabello-Verrugio, C, Moya-Alvarado, G, Tapia, JC, Valenzuela, V, Hetz, C, Bronfman, FC & Henríquez, JP 2019, 'The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability', Acta neuropathologica communications, vol. 7, n.º 1. https://doi.org/10.1186/s40478-019-0802-7

The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability. / Pérez, Viviana; Bermedo-Garcia, Francisca; Zelada, Diego; Court, Felipe A.; Pérez, Miguel Ángel; Fuenzalida, Marco; Ábrigo, Johanna; Cabello-Verrugio, Claudio; Moya-Alvarado, Guillermo; Tapia, Juan Carlos; Valenzuela, Vicente; Hetz, Claudio; Bronfman, Francisca C.; Henríquez, Juan Pablo.

En: Acta neuropathologica communications, Vol. 7, N.º 1, 12.09.2019.

Resultado de la investigación: Article

TY - JOUR

T1 - The p75NTR neurotrophin receptor is required to organize the mature neuromuscular synapse by regulating synaptic vesicle availability

AU - Pérez, Viviana

AU - Bermedo-Garcia, Francisca

AU - Zelada, Diego

AU - Court, Felipe A.

AU - Pérez, Miguel Ángel

AU - Fuenzalida, Marco

AU - Ábrigo, Johanna

AU - Cabello-Verrugio, Claudio

AU - Moya-Alvarado, Guillermo

AU - Tapia, Juan Carlos

AU - Valenzuela, Vicente

AU - Hetz, Claudio

AU - Bronfman, Francisca C.

AU - Henríquez, Juan Pablo

PY - 2019/9/12

Y1 - 2019/9/12

N2 - The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

AB - The coordinated movement of organisms relies on efficient nerve-muscle communication at the neuromuscular junction. After peripheral nerve injury or neurodegeneration, motor neurons and Schwann cells increase the expression of the p75NTR pan-neurotrophin receptor. Even though p75NTR targeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTR inhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTR null mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTR null mice show impaired postsynaptic organization and ultrastructural complexity, which correlate with altered synaptic function at the levels of nerve activity-induced muscle responses, muscle fiber structure, force production, and locomotor performance. Our results on primary myotubes and denervated muscles indicate that muscle-derived p75NTR does not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTR null mice display a strong reduction in the number of synaptic vesicles and active zones. According to the observed pre and postsynaptic defects, pharmacological acetylcholinesterase inhibition rescued nerve-dependent muscle response and force production in p75NTR null mice. Our findings revealing that p75NTR is required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.

KW - Motor neuron

KW - Neuromuscular junction

KW - Neurotrophin

KW - p75NTR

KW - Synaptic vesicles

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DO - 10.1186/s40478-019-0802-7

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