Glycosylated synaptomatrix regulation of trans-synaptic signaling

Synapse formation is driven by precisely orchestrated intercellular communication between the presynaptic and the postsynaptic cell, involving a cascade of anterograde and retrograde signals. At the neuromuscular junction (NMJ), both neuron and muscle secrete signals into the heavily glycosylated synaptic cleft matrix sandwiched between the two synapsing cells. These signals must necessarily traverse and interact with the extracellular environment, for the ligand-receptor interactions mediating communication to occur. This complex synaptomatrix, rich in glycoproteins and proteoglycans, comprises heterogeneous, compartmentalized domains where specialized glycans modulate trans-synaptic signaling during synaptogenesis and subsequent synapse modulation. The general importance of glycans during development, homeostasis and disease is well established, but this important molecular class has received less study in the nervous system. Glycan modifications are now understood to play functional and modulatory roles as ligands and co-receptors in numerous tissues; however, roles at the synapse are relatively unexplored. We highlight here properties of synaptomatrix glycans and glycan-interacting proteins with key roles in synaptogenesis, with a particular focus on recent advances made in the Drosophila NMJ genetic system. We discuss open questions and interesting new findings driving this investigation of complex, diverse, and largely understudied glycan mechanisms at the synapse.