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.
Highlights
There is evidence to suggest that several presynaptic receptors (muscarinic acetylcholine autoreceptors, adenosine autoreceptors (AR) and tropomyosin-related kinase B receptor (TrkB)) play an important role by allowing the nerve terminals to communicate in the competition that leads to synapse loss in the neuromuscular junction (NMJ) (Santafé et al, 2006; Amaral and Pozzo-Miller, 2012; Nadal et al, 2016)
Our results indicate that the weakest nerve endings (those that evoke endplate potentials (EPP) with the least quantal content in dual junctions) have an ACh release inhibition mechanism, based on muscarinic autoreceptors and coupled to protein kinase C (PKC) and voltage-dependent calcium channels (VDCC), that can depress the ACh release capacity in these endings and even contribute to functionally disconnect the synapse (Santafé et al, 2003, 2004, 2007a, 2009a,b; Tomàs et al, 2011)
We suggest that this muscarinic ‘‘mechanism plays a central role in the elimination of redundant neonatal synapses because functional axonal withdrawal can be temporarily reversed by muscarinic acetylcholine receptor (mAChR), VDCC or PKC block’’ (Santafé et al, 2007b, 2009a; Tomàs et al, 2011)
Summary
‘‘During the development of the nervous system there is an initial overproduction of synapses’’ (Lanuza et al, 2014) that promotes wide-ranging connectivity and which is followed by an activity-dependent reduction in their number (Thompson, 1985; Bourgeois and Rakic, 1993). ‘‘This refines connectivity and increases specificity’’ (Nadal et al, 2016). ‘‘at P9, neurotrophin signaling seems to reverse their coupling to the axonal loss process (Figure 3) because TrkB-Fc considerably delays elimination (resulting in more dual and fewer monoinnervated NMJs), which indicates that in a normal situation the role of BDNF/NT-4 mediators changes at this time (P9) and accelerates elimination, as has been described above for the muscarinic mechanism’’ (Nadal et al, 2016). Mice deficient in ‘‘P/Qtype Ca2+ channel have persistent multiple CF innervation on the PC soma’’ (Miyazaki et al, 2004) This fact agrees with our observation that, in the NMJ, a fraction of the Ca2+ entry through the P/Q-, N- or L-type VDCC reduces ACh release in the weak endings of dual junctions (Santafé et al, 2009a) relating Ca2+ inflow, transmitter release and synapse loss. LN, EH, AS, VC and MT: data collection, quantitative analysis; literature search, data interpretation, design graphic; NG, MAL and MMS: statistics; JT, NG, MAL and MMS: conception and design, literature search, data interpretation, manuscript preparation
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