Abstract
Background: During neuromuscular junction (NMJ) development, synapses are produced in excess. By sensing the activity-dependent release of ACh, adenosine, and neurotrophins, presynaptic receptors prompt axonal competition and loss of the unnecessary axons. The receptor action is mediated by synergistic and antagonistic relations when they couple to downstream kinases (mainly protein kinases A and C (PKA and PKC)), which phosphorylate targets involved in axonal disconnection. Here, we directly investigated the involvement of PKA subunits and PKC isoforms in synapse elimination. Methods: Selective PKA and PKC peptide modulators were applied daily to the Levator auris longus (LAL) muscle surface of P5–P8 transgenic B6.Cg-Tg (Thy1-YFP) 16 Jrs/J (and also C57BL/6J) mice, and the number of axons and the postsynaptic receptor cluster morphology were evaluated in P9 NMJ. Results: PKA (PKA-I and PKA-II isozymes) acts at the pre- and postsynaptic sites to delay both axonal elimination and nAChR cluster differentiation, PKC activity promotes both axonal loss (a cPKCβI and nPKCε isoform action), and postsynaptic nAChR cluster maturation (a possible role for PKCθ). Moreover, PKC-induced changes in axon number indirectly influence postsynaptic maturation. Conclusions: PKC and PKA have opposed actions, which suggests that changes in the balance of these kinases may play a major role in the mechanism of developmental synapse elimination.
Highlights
During the histogenesis of the nervous system, both neurons and synapses are produced in excess.Subsequent refinement occurs throughout the nervous system [1,2,3] and leads to maturation, improves function, and ensures that the appropriated connections remain, whereas the redundant ones are eliminated [4,5,6].At birth, neuromuscular junctions (NMJs) are polyinnervated but, by the end of axonal competition, the motor endplates are innervated by only one axon [6,7,8,9,10,11]
NMJs in all stages of maturation can be observed during this period, and axonal elimination is accompanied by the morphological differentiation of the postsynaptic component
We hypothesize that the prevalence of a protein kinase C (PKC)-mediated mechanism in some endings contributes to their destabilization and retraction
Summary
During the histogenesis of the nervous system, both neurons and synapses are produced in excess.Subsequent refinement occurs throughout the nervous system [1,2,3] and leads to maturation, improves function, and ensures that the appropriated connections remain, whereas the redundant ones are eliminated [4,5,6].At birth, neuromuscular junctions (NMJs) are polyinnervated but, by the end of axonal competition, the motor endplates are innervated by only one axon [6,7,8,9,10,11]. Activity-dependent signaling through membrane receptors enables axon terminals and synapses to influence each other directly or through the postsynaptic component and neighbor glial cells [12,13,14,15]. The receptor action is mediated by synergistic and antagonistic relations when they couple to downstream kinases (mainly protein kinases A and C (PKA and PKC)), which phosphorylate targets involved in axonal disconnection. We directly investigated the involvement of PKA subunits and PKC isoforms in synapse elimination. Results: PKA (PKA-I and PKA-II isozymes) acts at the pre- and postsynaptic sites to delay both axonal elimination and nAChR cluster differentiation, PKC activity promotes both axonal loss (a cPKCβI and nPKCε isoform action), and postsynaptic nAChR cluster maturation (a possible role for PKCθ). Conclusions: PKC and PKA have opposed actions, which suggests that changes in the balance of these kinases may play a major role in the mechanism of developmental synapse elimination
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