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      Presynaptic Membrane Receptors Modulate ACh Release, Axonal Competition and Synapse Elimination during Neuromuscular Junction Development

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          Abstract

          During the histogenesis of the nervous system a lush production of neurons, which establish an excessive number of synapses, is followed by a drop in both neurons and synaptic contacts as maturation proceeds. Hebbian competition between axons with different activities leads to the loss of roughly half of the neurons initially produced so connectivity is refined and specificity gained. The skeletal muscle fibers in the newborn neuromuscular junction (NMJ) are polyinnervated but by the end of the competition, 2 weeks later, the NMJ are innervated by only one axon. This peripheral synapse has long been used as a convenient model for synapse development. In the last few years, we have studied transmitter release and the local involvement of the presynaptic muscarinic acetylcholine autoreceptors (mAChR), adenosine autoreceptors (AR) and trophic factor receptors (TFR, for neurotrophins and trophic cytokines) during the development of NMJ and in the adult. This review article brings together previously published data and proposes a molecular background for developmental axonal competition and loss. At the end of the first week postnatal, these receptors modulate transmitter release in the various nerve terminals on polyinnervated NMJ and contribute to axonal competition and synapse elimination.

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          Most cited references96

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          Development of the vertebrate neuromuscular junction.

          We describe the formation, maturation, elimination, maintenance, and regeneration of vertebrate neuromuscular junctions (NMJs), the best studied of all synapses. The NMJ forms in a series of steps that involve the exchange of signals among its three cellular components--nerve terminal, muscle fiber, and Schwann cell. Although essentially any motor axon can form NMJs with any muscle fiber, an additional set of cues biases synapse formation in favor of appropriate partners. The NMJ is functional at birth but undergoes numerous alterations postnatally. One step in maturation is the elimination of excess inputs, a competitive process in which the muscle is an intermediary. Once elimination is complete, the NMJ is maintained stably in a dynamic equilibrium that can be perturbed to initiate remodeling. NMJs regenerate following damage to nerve or muscle, but this process differs in fundamental ways from embryonic synaptogenesis. Finally, we consider the extent to which the NMJ is a suitable model for development of neuron-neuron synapses.
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            Changes of synaptic density in the primary visual cortex of the macaque monkey from fetal to adult stage.

            The kinetics of synaptogenesis in the primary visual cortex (Brodmann's area 17) were analyzed by electron microscopy in 33 rhesus monkeys, ranging in age from the 50th embryonic day (E50) to 20 years. A series of overlapping electron micrographs (vertical probes) were examined at each age on sections of the upper bank of the calcarine fissure. Synaptic contacts were first observed in the E50 specimen in the subplate and marginal zone (prospective layer I). In the cortical plate itself, synapses appear between E65 and E89 starting in the prospective layer VI. By E112, after all cortical neurons have assumed their laminar positions, synapses situated predominantly on dendritic shafts were present at a low density throughout the full thickness of the cortical plate. Thereafter, synapses accumulate more rapidly on dendritic spines and by E144 an equal number of contacts are found on both spines and shafts. The density of synapses continues to increase exponentially in all layers and reaches the mean maximum density of about 90 synapses per 100 microns 3 of neuropil by the third postnatal month. During the next 2 postnatal years the density of synaptic contacts decreases only slightly to a mean of 80/100 microns 3 of neuropil. Around the time of puberty, however, synaptic density decreases more rapidly to reach the adult level of about 40-50/100 microns 3 of neuropil. The 40% decrease in the density of synaptic contacts occurring between 2.7 and 5 years represents a loss of about 5000 synapses per second in the primary visual cortex of the two hemispheres, due primarily to the loss of asymmetric synapses situated on dendritic spines. The transient phase of high density of synaptic contacts located on dendrospines is shorter in thalamo-recipient layer IV than in either supra- or intragranular layers and is completed within the first postnatal year. It ends earlier in sublayer IVC than in layers IVAB and II-III, for example, reflecting biochemical and functional maturation of the different visual subsystems.
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              Roles for the pro-neurotrophin receptor sortilin in neuronal development, aging and brain injury.

              Neurotrophins are essential for development and maintenance of the vertebrate nervous system. Paradoxically, although mature neurotrophins promote neuronal survival by binding to tropomyosin receptor kinases and p75 neurotrophin receptor (p75(NTR)), pro-neurotrophins induce apoptosis in cultured neurons by engaging sortilin and p75(NTR) in a death-signaling receptor complex. Substantial amounts of neurotrophins are secreted in pro-form in vivo, yet their physiological significance remains unclear. We generated a sortilin-deficient mouse to examine the contribution of the p75(NTR)/sortilin receptor complex to neuronal viability. In the developing retina, Sortilin 1 (Sort1)(-/-) mice showed reduced neuronal apoptosis that was indistinguishable from that observed in p75(NTR)-deficient (Ngfr(-/-)) mice. To our surprise, although sortilin deficiency did not affect developmentally regulated apoptosis of sympathetic neurons, it did prevent their age-dependent degeneration. Furthermore, in an injury protocol, lesioned corticospinal neurons in Sort1(-/-) mice were protected from death. Thus, the sortilin pathway has distinct roles in pro-neurotrophin-induced apoptotic signaling in pathological conditions, but also in specific stages of neuronal development and aging.
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                Author and article information

                Contributors
                Journal
                Front Mol Neurosci
                Front Mol Neurosci
                Front. Mol. Neurosci.
                Frontiers in Molecular Neuroscience
                Frontiers Media S.A.
                1662-5099
                16 May 2017
                2017
                : 10
                : 132
                Affiliations
                [1]Unitat d’Histologia i Neurobiologia (UHN), Facultat de Medicina i Ciències de la Salut, Universitat Rovira i Virgili Reus, Spain
                Author notes

                Edited by: Chen Zhang, Peking University, China

                Reviewed by: Osvaldo D. Uchitel, University of Buenos Aires, Argentina; Hyunsoo Shawn JE, Duke NUS Graduate Medical School, Singapore

                These authors have contributed equally to this work.

                Article
                10.3389/fnmol.2017.00132
                5432534
                ae2a2f3a-b332-4737-a29e-a1073e9e2e58
                Copyright © 2017 Tomàs, Garcia, Lanuza, Santafé, Tomàs, Nadal, Hurtado, Simó and Cilleros.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 February 2017
                : 20 April 2017
                Page count
                Figures: 4, Tables: 0, Equations: 0, References: 101, Pages: 12, Words: 10704
                Funding
                Funded by: Generalitat de Catalunya 10.13039/501100002809
                Award ID: 2014SGR344
                Funded by: Ministerio de Economà­a y Competitividad 10.13039/501100003329
                Award ID: SAF2015-67143-P
                Categories
                Neuroscience
                Review

                Neurosciences
                postnatal synapse elimination,axonal competition,acetylcholine release,voltage-dependent calcium channels,muscarinic acetylcholine receptors,protein kinases,trkb,pkc

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