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 p75NTRpan-neurotrophin receptor. Even though p75NTRtargeting has emerged as a promising therapeutic strategy to delay peripheral neuronal damage progression, the effects of long-term p75NTRinhibition at the mature neuromuscular junction have not been elucidated. We performed quantitative neuroanathomical analyses of the neuromuscular junction in p75NTRnull mice by laser confocal and electron microscopy, which were complemented with electromyography, locomotor tests, and pharmacological intervention studies. Mature neuromuscular synapses of p75NTRnull 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 p75NTRdoes not play a major role on postsynaptic organization. In turn, motor axon terminals of p75NTRnull 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 p75NTRnull mice. Our findings revealing that p75NTRis required to organize mature neuromuscular junctions contribute to a comprehensive view of the possible effects caused by therapeutic attempts to target p75NTR.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Sep 12, 2019
- Source ID
- 10.1186/s40478-019-0802-7
Entities
People
- Claudio Cabello-verrugio
- Claudio Hetz
- Diego Zelada
- Felipe A. Court
- Francisca Bermedo-garcia
- Francisca C. Bronfman
- Guillermo Moya-alvarado
- Johanna Ábrigo
- Juan Carlos Tapia
- Juan Pablo Henriquez
- Marco Fuenzalida
- Miguel Ángel Pérez
- Vicente Valenzuela
- Viviana Pérez
Organizations
- ALS Association
- Air Force Office of Scientific Research
- FONDEF
- Millennium Institute
- Muscular Dystrophy Association
- National Fund for Scientific and Technological Development
- Office of Naval Research Global