title: Presynaptic muscarinic acetylcholine autoreceptors (M1, M2 and M4 subtypes), adenosine receptors (A1 and A2A) and tropomyosin-related kinase B receptor (TrkB) modulate the developmental synapse elimination process at the neuromuscular junction.
abstract: The development of the nervous system involves an initially exuberant production of neurons that make an excessive number of synaptic contacts. The initial overproduction of synapses promotes connectivity. Hebbian competition between axons with different activities (the least active are punished) leads to the loss of roughly half of the overproduced elements and this refines connectivity and increases specificity. The neuromuscular junction is innervated by a single axon at the end of the synapse elimination process and, because of its relative simplicity, has long been used as a model for studying the general principles of synapse development. The involvement of the presynaptic muscarinic ACh autoreceptors may allow for the direct competitive interaction between nerve endings through differential activity-dependent acetylcholine release in the synaptic cleft. Then, the most active ending may directly punish the less active ones. Our previous results indicate the existence in the weakest axons on the polyinnervated neonatal NMJ of an ACh release inhibition mechanism based on mAChR coupled to protein kinase C and voltage-dependent calcium channels. We suggest that this mechanism plays a role in the elimination of redundant neonatal synapses.
  
  
  
  Here we used confocal microscopy and quantitative morphological analysis to count the number of brightly fluorescent axons per endplate in P7, P9 and P15 transgenic B6.Cg-Tg (Thy1-YFP)16 Jrs/J mice. We investigate the involvement of individual mAChR M1-, M2- and M4-subtypes in the control of axonal elimination after the Levator auris longus muscle had been exposed to agonist and antagonist in vivo. We also analysed the role of adenosine receptor subtypes (A1 and A2A) and the tropomyosin-related kinase B receptor. The data show that postnatal axonal elimination is a regulated multireceptor mechanism that guaranteed the monoinnervation of the neuromuscular synapses.
  
  
  
  The three receptor sets considered (mAChR, AR and TrkB receptors) intervene in modulating the conditions of the competition between nerve endings, possibly helping to determine the winner or the lossers but, thereafter, the final elimination would occur with some autonomy and independently of postsynaptic maturation.
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Nadal
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain. mariadelesneus.garcia@urv.cat.
authors.forename: Neus
authors.initials: N
authors.lastname: Garcia
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain.
authors.forename: Erica
authors.initials: E
authors.lastname: Hurtado
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Simó
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Tomàs
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Lanuza
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Santafé
authors.affiliation: Unitat d'Histologia i Neurobiologia (UHN): Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili, Carrer St Llorenç num 21, 43201, Reus, Spain. josepmaria.tomas@urv.cat.
authors.forename: Josep
authors.initials: J
authors.lastname: Tomàs
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001285:Atropine / Q000494:pharmacology; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005455:Fluorescent Antibody Technique; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D009469:Neuromuscular Junction / Q000187:drug effects / Q000378:metabolism*; D010095:Oxotremorine / Q000494:pharmacology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism*; D020813:Receptor, trkB / Q000378:metabolism*; D011976:Receptors, Muscarinic / Q000378:metabolism*; D018047:Receptors, Purinergic P1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D011976:Receptors, Muscarinic; D018047:Receptors, Purinergic P1; D010095:Oxotremorine; D001285:Atropine; D020813:Receptor, trkB
keywords: Cholinergic synapses; Motor end-plate; Motor nerve terminal; Neuromuscular junction