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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| 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 |
| Sumario: | 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. |
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