Building the vertebrate neuromuscular synapse.

Abstract

Neuromuscular synapses form following a series of complex interactions between motor neurons, muscle fibers, and Schwann cells that culminate in the formation of a highly specialized postsynaptic membrane and a highly differentiated nerve terminal (Son and Thompson, 1995; Burden, 1998; Sanes and Lichtman, 2001; Schaeffer et al., 2001). In adult muscle, motor axon terminals are situated in shallow depressions of the muscle cell membrane, which is invaginated further into deep and regular folds, termed postjunctional folds. Acetylcholine receptors (AChRs) and additional proteins are concentrated at the crests of these postjunctional folds, while other proteins, including sodium channels, are enriched in the troughs of the postjunctional folds. The genes encoding many of these muscle-derived synaptic proteins are transcribed preferentially in the myofiber nuclei that are situated near the synaptic site, resulting in an accumulation of the encoded mRNAs near synaptic nuclei. The nerve terminal is likewise spatially organized, and its substructural organization reflects that of the postsynaptic membrane. Synaptic vesicles are clustered adjacent to poorly characterized specializations of the presynaptic membrane, termed active zones, which are the sites of synaptic vesicle fusion. Active zones are organized at regular intervals and are aligned precisely with the mouths of the postjunctional folds. This precise registration of active zones and postjunctional folds insures that acetylcholine encounters a high concentration of AChRs within microseconds after release, thereby facilitating synaptic transmission. This precise organization of molecules in presynaptic and postsynaptic membranes belies the concept that the neuromuscular synapse is a simple synapse. Rather, the substructure of presynaptic and postsynaptic membranes suggests that complex mechanisms, requiring spatially restricted signaling between presynaptic and postsynaptic cells, are required to assemble the synapse and to coordinate presynaptic and postsynaptic differentiation.