Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction

The neuromuscular junction (NMJ) is a peripheral cholinergic synapse formed between a motor axon, a skeletal muscle fiber, and terminal Schwann cells. The maturation of the NMJ includes a morphological, structural and functional refinement of this synapse allowing controlled muscle contraction. Howe...

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Autor: Pérez-Fenández, Viviana Ivonne
Tipo de recurso: tesis doctoral
Estado:Versión publicada
Fecha de publicación:2018
País:Chile
OAI Identifier:oai:repositorio.anid.cl:10533/220346
Acceso en línea:https://hdl.handle.net/10533/220346
Access Level:acceso abierto
Palabra clave:Ciencias Naturales
Otras Ciencias Naturales
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dc.title.es_CL.fl_str_mv Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
Estudio de la funcion del receptor de neurotrofinas p75 sobre la maduracion de la union neuromuscular adulta
title Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
spellingShingle Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
Pérez-Fenández, Viviana Ivonne
Ciencias Naturales
Otras Ciencias Naturales
title_short Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
title_full Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
title_fullStr Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
title_full_unstemmed Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
title_sort Study of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junction
dc.creator.none.fl_str_mv Pérez-Fenández, Viviana Ivonne
author Pérez-Fenández, Viviana Ivonne
author_facet Pérez-Fenández, Viviana Ivonne
author_role author
dc.contributor.advisor.none.fl_str_mv Henríquez-Hohmann, Juan Pablo
dc.contributor.institution.es_CL.fl_str_mv UNIVERSIDAD DE CONCEPCION
dc.subject.oecd1n.es_CL.fl_str_mv Ciencias Naturales
topic Ciencias Naturales
Otras Ciencias Naturales
dc.subject.oecd2n.es_CL.fl_str_mv Otras Ciencias Naturales
description The neuromuscular junction (NMJ) is a peripheral cholinergic synapse formed between a motor axon, a skeletal muscle fiber, and terminal Schwann cells. The maturation of the NMJ includes a morphological, structural and functional refinement of this synapse allowing controlled muscle contraction. However, the mechanisms that control the maturation of the NMJ have not been well described. A signaling pathway that regulates the maintenance and function of the neuromuscular synapse is the neurotrophin pathway, whose p75 receptor is expressed in the three components of the adult NMJ. Although it has been described that the p75 receptor favors synaptic transmission, its possible function in the maturation of this synapse is unknown. To determine if the p75 neurotrophin receptor is required for the maturation of the NMJ, we have characterized neuromuscular, motor and muscle properties of the mouse p75 knockout mice (p75-/-). Analyses through 3D confocal microscopy and electron microscopy indicate that the absence of the p75 receptor results in a delay in the maturation and impaired ultrastructural complexity of the postsynaptic apparatus at the NMJ. Ultrastructural analyses of the motor axon terminal reveal a significant reduction in the number of synaptic vesicles in the mutants, suggesting a lower availability of the neurotransmitter. The structural NMJ defects found in p75-/- mice correlate with alterations in motor behavior, deficiencies in muscle contractile properties, failures in neuromuscular transmission and muscle weakness. Additionally, the results suggest that p75 expressed in the muscle do not contribute directly to thexxi aggregation of the AChR nor morphology of the aggregates, evaluated by primary cultures of muscle satellite cells and subsequent analysis aggregation of the AChR on the formed myotubes. Therefore, the results suggest that presynaptic defects contribute directly to the phenotype found in p75 -/- mice. Accordingly, pharmacological treatment with an acetylcholinesterase inhibitor reverses the motor disruption and muscle weakness in p75-/- mice, suggesting that the decrease in synaptic vesicles contributes to the alterations found in these mice. Our results suggest that the p75 neurotrophin receptor is required for the maturation of the NMJ, allowing the availability of synaptic vesicles in the axonal terminal, thereby regulating the morphology and function of neuromuscular connectivity.
publishDate 2018
dc.date.accessioned.none.fl_str_mv 2018-09-12T20:15:38Z
2022-08-16T20:06:27Z
dc.date.available.none.fl_str_mv 2018-09-12T20:15:38Z
2022-08-16T20:06:27Z
dc.date.issued.es_CL.fl_str_mv 2018
dc.type.none.fl_str_mv Tesis Doctorado
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spelling UNIVERSIDAD DE CONCEPCIONPérez-Fenández, Viviana Ivonne2018https://hdl.handle.net/10533/220346http://purl.org/coar/access_right/c_abf2Otras Ciencias NaturalesCiencias NaturalesStudy of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junctionHenríquez-Hohmann, Juan PabloUNIVERSIDAD DE CONCEPCIONCHILEPérez-Fenández, Viviana Ivonne2018-09-12T20:15:38Z2022-08-16T20:06:27Z2018-09-12T20:15:38Z2022-08-16T20:06:27Z2018The neuromuscular junction (NMJ) is a peripheral cholinergic synapse formed between a motor axon, a skeletal muscle fiber, and terminal Schwann cells. The maturation of the NMJ includes a morphological, structural and functional refinement of this synapse allowing controlled muscle contraction. However, the mechanisms that control the maturation of the NMJ have not been well described. A signaling pathway that regulates the maintenance and function of the neuromuscular synapse is the neurotrophin pathway, whose p75 receptor is expressed in the three components of the adult NMJ. Although it has been described that the p75 receptor favors synaptic transmission, its possible function in the maturation of this synapse is unknown. To determine if the p75 neurotrophin receptor is required for the maturation of the NMJ, we have characterized neuromuscular, motor and muscle properties of the mouse p75 knockout mice (p75-/-). Analyses through 3D confocal microscopy and electron microscopy indicate that the absence of the p75 receptor results in a delay in the maturation and impaired ultrastructural complexity of the postsynaptic apparatus at the NMJ. Ultrastructural analyses of the motor axon terminal reveal a significant reduction in the number of synaptic vesicles in the mutants, suggesting a lower availability of the neurotransmitter. The structural NMJ defects found in p75-/- mice correlate with alterations in motor behavior, deficiencies in muscle contractile properties, failures in neuromuscular transmission and muscle weakness. Additionally, the results suggest that p75 expressed in the muscle do not contribute directly to thexxi aggregation of the AChR nor morphology of the aggregates, evaluated by primary cultures of muscle satellite cells and subsequent analysis aggregation of the AChR on the formed myotubes. Therefore, the results suggest that presynaptic defects contribute directly to the phenotype found in p75 -/- mice. Accordingly, pharmacological treatment with an acetylcholinesterase inhibitor reverses the motor disruption and muscle weakness in p75-/- mice, suggesting that the decrease in synaptic vesicles contributes to the alterations found in these mice. Our results suggest that the p75 neurotrophin receptor is required for the maturation of the NMJ, allowing the availability of synaptic vesicles in the axonal terminal, thereby regulating the morphology and function of neuromuscular connectivity.La unión neuromuscular (UNM) es una sinapsis periférica colinérgica formada entre un axón motor, una fibra muscular esquelética y células de Schwann terminales. La maduración de la UNM comprende un refinamiento morfológico, estructural y funcional de esta sinapsis permitiendo la contracción muscular controlada. Sin embargo, los mecanismos que controlan la maduración de la UNM no han sido bien descritos. Una vía de señalización que controla la mantención y función de la sinapsis neuromuscular es la vía de las neurotrofinas, cuyo receptor p75 es expresado en los tres componentes de la UNM adulta. Aunque se ha descrito que el receptor p75 favorece la trasmisión sináptica, su posible función en la maduración de esta sinapsis es desconocida. Para determinar si el receptor de neurotrofinas p75 es requerido para la maduración de la UNM, hemos caracterizado propiedades neuromusculares, motoras y musculares del ratón p75 knockout (p75-/-). Los resultados obtenidos mediante análisis de microscopía confocal 3D y microscopía electrónica indican que la ausencia del receptor p75 produce un retraso en la maduración y menor complejidad ultraestructural del aparato postsináptico de la UNM. Análisis ultraestructurales del terminal axonal motor revelan una significativa reducción en el número de vesículas sinápticas en los mutantes, sugiriendo una menor disponibilidad del neurotransmisor. Dichos defectos estructurales encontrados en ratones p75-/- se correlacionan con alteraciones en el comportamiento motor, deficiencias en propiedades contráctiles musculares, fallas en la transmisiónxix neuromuscular y debilidad muscular. Adicionalmente, los resultados sugieren que p75 expresado en el músculo no contribuye de manera directa a la agregación del AChR ni su morfología de los agregados, evaluado mediante cultivos primarios de células satélites musculares y análisis de agregación del AChR sobre los miotubos formados. Por lo tanto, los resultados sugieren que defectos presinápticos contribuyen directamente al fenotipo encontrado en los ratones p75 -/-. Concordantemente, el tratamiento farmacológico con un inhibidor de la acetilcolinesterasa, revierte la descoordinación motora y debilidad muscular en los ratones p75-/-, sugiriendo que la disminución de vesículas sinápticas contribuye a las alteraciones encontradas en estos ratones. Nuestros resultados sugieren que el receptor de neurotrofinas p75 es requerido para la maduración de la UNM, permitiendo la disponibilidad de vesículas sinápticas en el terminal axonal, regulando con ello la morfología y función de la conectividad neuromuscular.21120211https://hdl.handle.net/10533/220346instname: Conicytreponame: Repositorio Digital RI2.0info:eu-repo/grantAgreement//81130168info:eu-repo/grantAgreement//81130168info:eu-repo/grantAgreement//81130168info:eu-repo/grantAgreement//21120211info:eu-repo/semantics/dataset/hdl.handle.net/10533/93488info:eu-repo/semantics/openAccessCC0 1.0 Universalhttp://creativecommons.org/publicdomain/zero/1.0/Ciencias NaturalesOtras Ciencias NaturalesStudy of the function of p75 neurotrophin receptor on the maturation of adult neuromuscular junctionEstudio de la funcion del receptor de neurotrofinas p75 sobre la maduracion de la union neuromuscular adultaTesis Doctoradoinfo:eu-repo/semantics/doctoralThesisinfo:eu-repo/semantics/publishedVersionTesisTesishttps://hdl.handle.net/10533/220346ddfa9809-a022-4a44-a3f5-3dad49dd94c6virtual::57490-1ddfa9809-a022-4a44-a3f5-3dad49dd94c6virtual::57490-1CC-LICENSElicense_rdfapplication/octet-stream1089https://repositorio.anid.cl/bitstreams/b7c2df8c-d6e5-4197-a366-b4445ab3c3fb/download0a703d871bf062c5fdc7850b1496693bMD51LICENSElicense.txttext/plain1779https://repositorio.anid.cl/bitstreams/9106b296-060c-4aae-9c0d-6e8374755087/download593a6e7305c66c56041a9f9e15a649c1MD52ORIGINALperezviviana_prog4235.pdfapplication/pdf6015221https://repositorio.anid.cl/bitstreams/334202d2-1155-41d2-b8d9-21248c9504c5/download53f8cff1e11d4b2d69f887db6a7bb4d4MD53TEXTperezviviana_prog4235.pdf.txtExtracted texttext/plain323153https://repositorio.anid.cl/bitstreams/d22de7c4-abf1-4322-a602-9fc346cb1a8e/download70044941ad0a4a920cf5515b83bdb1a4MD54THUMBNAILperezviviana_prog4235.pdf.jpgIM Thumbnailimage/jpeg2356https://repositorio.anid.cl/bitstreams/aae9e2c4-8647-4028-841d-1560468e09c0/download5889af2b093d842dd5a000fae347cdd7MD5510533/220346oai:repositorio.anid.cl:10533/2203462023-07-24 16:26:20.411http://creativecommons.org/publicdomain/zero/1.0/info:eu-repo/semantics/openAccesshttps://repositorio.anid.clRepositorio ANIDaletelier@anid.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