Abstract
Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined. Membrane receptor signaling leads to activity-dependent mutual influence and competition between axons directly or with the involvement of the postsynaptic cell and the associated glial cell/s. Presynaptic muscarinic acetylcholine (ACh) receptors (subtypes mAChR; M1, M2 and M4), adenosine receptors (AR; A1 and A2A) and the tropomyosin-related kinase B receptor (TrkB), among others, all cooperate in synapse elimination. Between these receptors there are several synergistic, antagonic and modulatory relations that clearly affect synapse elimination. Metabotropic receptors converge in a limited repertoire of intracellular effector kinases, particularly serine protein kinases A and C (PKA and PKC), to phosphorylate protein targets and bring about structural and functional changes leading to axon loss. In most cells A1, M1 and TrkB operate mainly by stimulating PKC whereas A2A, M2 and M4 inhibit PKA. We hypothesize that a membrane receptor-induced shifting in the protein kinases A and C activity (inhibition of PKA and/or stimulation of PKC) in some nerve endings may play an important role in promoting developmental synapse elimination at the neuromuscular junction (NMJ). This hypothesis is supported by: (i) the tonic effect (shown by using selective inhibitors) of several membrane receptors that accelerates axon loss between postnatal days P5–P9; (ii) the synergistic, antagonic and modulatory effects (shown by paired inhibition) of the receptors on axonal loss; (iii) the fact that the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv) the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the mAChR, AR and TrkB receptors. The use of transgenic animals and various combinations of selective and specific PKA and PKC inhibitors could help to elucidate the role of these kinases in synapse maturation.
Highlights
Synapses that are overproduced during histogenesis in the nervous system are eventually lost and connectivity is refined
protein kinase A (PKA) and protein kinase C (PKC) in Postnatal Synapse Elimination the coupling of these receptors activates/inhibits the intracellular serine kinases; and (iv) the increase of the PKA activity, the reduction of the PKC activity or, in most cases, both situations simultaneously that presumably occurs in all the situations of singly and paired inhibition of the muscarinic acetylcholine receptors (mAChR), adenosine receptors (AR) and tropomyosin-related kinase B receptor (TrkB) receptors
We observed that presynaptic muscarinic acetylcholine receptors, adenosine receptors (AR; A1 and A2A) and the neurotrophin receptor (NTR) tropomyosin-related kinase B receptor (TrkB) all cooperate in the developmental synapse elimination process at this synapse [neuromuscular junction (NMJ) from the Levator auris longus—Levator auris longus muscle (LAL)—muscle of the B6.Cg-Tg (Thy1YFP)16 Jrs/J mice, and from C57BL/6J P7 mice] by favoring axonal competition and loss (Nadal et al, 2016a,b, 2017; Tomàs et al, 2017)
Summary
When the nervous system develops, the neurons and synapses involved in circuitry wiring and connectivity are overproduced. Hebbian competition between nerve processes and endings eliminates redundant synapses and refines the specificity of the functional circuits (Purves and Lichtman, 1980; Jansen and Fladby, 1990; Sanes and Lichtman, 1999). The NMJs are initially polyinnervated but, by the end of the axonal competition, the motor endplates are innervated by a solitary axon (Benoit and Changeux, 1975; O’Brien et al, 1978; Liu et al, 1994; Ribchester and Barry, 1994; Nguyen and Lichtman, 1996; Chang and BaliceGordon, 1997; Sanes and Lichtman, 1999; Herrera and Zeng, 2003; Nelson et al, 2003; Wyatt and Balice-Gordon, 2003; Buffelli et al, 2004; Figure 1)
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