The role of Schwann cells in synapse formation and synaptic transmission at developing neuromuscular junctions

Recent evidence indicates that glial cells have broad, dynamic, bi-directional interactions with neurons, but our knowledge on the role of glial cells in the nervous system is still rudimental. Using vertebrate neuromuscular junction, a well-defined chemical synapse, we studied the role of Schwann cells in synapse formation and synaptic release. Firstly, we tested the hypothesis that Schwann cells play a role in the aggregation of acetylcholine receptors (AChRs) on muscle. We found that adult Xenopus Schwann cells enhanced the aggregation of AChRs on muscle in vitro, which was mediated by soluble factors released by Schwann cells. We found that Schwann cells expressed active agrin isoforms, and the enhancement of AChR aggregation by Schwann cells was blocked by heparin, suggesting that the aggregation of AChRs by Schwann cells was attributed to neural agrin released by Schwann cells. The enhancement of AChR aggregation by Schwann cells, as well as the agrin express in Schwann cells, was upregulated by neuronal degeneration. Therefore, the AChR aggregation induced by Schwann cells may play a role in the maintenance of postsynaptic apparatus and the restoration of synapse function after nerve injury.; Secondly, we tested if Schwann cells can acutely modulate synaptic release. We collected Schwann cell-conditioned medium (SC-CM) and applied it to developing neuromuscular synapses, and found that SC-CM enhanced the frequency of spontaneous synaptic release but inhibited the evoked synaptic release. The potentiation of spontaneous synaptic release by SC-CM is independent of neuronal action potential firing, and it is a presynaptic effect. The SC-CM effect requires the Ca2+ influx, which is mainly mediated by L-type Ca 2+ channels. Using soma removal and focal application techniques, we demonstrated that the functional sites of SC-CM were located on the neuron soma. The SC-CM effect is not attributed to any known factors, such as neurotrophins, prostaglandin, ATP and glutamate that have been proven to modulate synaptic activities. We also found that SC-CM increased the mEPP frequency at developing NMJs in situ, but not adult frog NMJs in vitro. Our results suggest that the modification of synaptic efficacy by Schwann cell-derived factors plays a role in the synaptogenesis of NMJs.; Therefore, our results demonstrate that Schwann cells are actively involved in both the synapse formation and the synaptic function of NMJs.