The Role of Glial Cells in the Formation and Maintenance of the Neuromuscular Junction

Abstract

The vertebrate neuromuscular junction (NMJ) is a "tripartite" synapse, composed of three cellular elements: the presynaptic nerve terminal, the postsynaptic specialization, and synapse-associated glial cells, called perisynaptic Schwann cells (PSCs; also called terminal Schwann cells). During development, PSCs grow beyond nerve terminals and guide nerve terminal extension. Nerve terminals retract or stop extension after PSC ablation by complement-mediated lysis in vivo, suggesting that PSCs can promote synaptic growth and maintenance at developing NMJs. Schwann cell-conditioned medium (SC-CM), which may be mediated by transforming growth factor-beta1, can promote synapse formation in Xenopus nerve-muscle culture. In addition, SC-CM contains small molecules (within 500-5000 Da), which can enhance spontaneous synaptic activities acutely and potently at developing frog NMJs. In adult muscles, PSCs can detect evoked synaptic activities and are capable of modulating transmitter release. Nerve terminals retract and synaptic efficacy is reduced at 1 week, but not within the first few hours, after PSC ablation. Thus, PSCs are essential for the long-term, but not short-term, maintenance of synaptic structure and function at the adult NMJ. During synaptic remodeling in adult muscles, PSC sprouts lead nerve terminal sprouts. After nerve injury, adult PSCs sprout extensive processes, which guide regenerating nerve terminals. Schwann cells express agrin and neuregulins, which may help the postsynaptic differentiation and synaptic repair. Furthermore, neuregulin-ErbB signaling pathways play an essential role in synapse-glial interactions at the NMJ. These recent findings suggest that PSCs play multiple roles and actively participate in synaptic development, modulation, maintenance, and repair of the vertebrate NMJ.