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

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.

Membrane Receptor-Induced Changes of the Protein Kinases A and C Activity May Play a Leading Role in Promoting Developmental Synapse Elimination at the Neuromuscular Junction

“…We simultaneously applied two inhibitors (two selective antagonists from two different receptors) to reveal the possible additive or occlusive crosstalk effects between the corresponding pathways. The histograms in Figure 2 show the individual and the paired effects of these inhibitors on axonal loss at P9 (percentage of the monoinnervated synapses after exposure to blockers (data drawn from previous studies: Nadal et al, 2016a , b , 2017 ; Tomàs et al, 2017 ). The paired inhibition data of the AR and TrkB shown in histograms i and j from Figure 2A have not been previously published).…”

“…Scale bar: 10 μm. Image (A) has been adapted from Figure 1 in the original article (Tomàs et al, 2017 ). The original article is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0 ), which permits unrestricted use, distribution and reproduction in any medium, provided the original work is properly cited.…”

“…Membrane receptor signaling can play a role in axonal competition by allowing the various nerve endings to have an activity-dependent influence on one another directly or with the involvement of the postsynaptic cell and the associated glial cell/s (Keller-Peck et al, 2001 ; Tomàs et al, 2014 ). We observed that presynaptic muscarinic acetylcholine receptors (mAChR; subtypes M 1 , M 2 and M 4 ), adenosine receptors (AR; A 1 and A 2A ) and the neurotrophin receptor (NTR) tropomyosin-related kinase B receptor (TrkB) all cooperate in the developmental synapse elimination process at this synapse [NMJ from the Levator auris longus —LAL—muscle of the B6.Cg-Tg (Thy1-YFP)16 Jrs/J mice (hereinafter YFP mice), and from C57BL/6J P7 mice] by favoring axonal competition and loss (Nadal et al, 2016a , b , 2017 ; Tomàs et al, 2017 ). Other receptors, for example glutamate receptors at the mice NMJ (Waerhaug and Ottersen, 1993 ) may collaborate because developmental synapse loss is slowed by reducing activation of the glutamate-NMDA receptor pathway (Personius et al, 2016 ).…”

The Impact of Kinases in Amyotrophic Lateral Sclerosis at the Neuromuscular Synapse: Insights into BDNF/TrkB and PKC Signaling

“…Consequently, in ALS, where TrkB.FL is downregulated, PKC activation is affected, yet at the presymptomatic stage in some isoforms [95], suggesting a profound and complex molecular implication in the progression of the disease. Furthermore, other presynaptic metabotropic receptors related with PLCβ (such as adenosine receptor A 1 and muscarinic receptor M 1 ) may contribute to the selective modulation of different PKC isoforms in the muscle, as their activity is also related with TrkB and PKC [127][128][129].…”

Adenosine Receptors in Developing and Adult Mouse Neuromuscular Junctions and Functional Links With Other Metabotropic Receptor Pathways

“…In the last few years, we have studied the presence and involvement of AR in the synaptogenesis and transmitter release in the developing and mature mammalian NMJ ( Garcia et al, 2013 ; Tomàs et al, 2014 ; Tomàs J. et al, 2017 ; Santafé et al, 2015 ; Nadal et al, 2016a , b , 2017 ). Here, we review and bring together previously published data to contribute to emphasizing the relevance of these receptors in this synapse.…”