O-GlcNAc transferase promotes synaptic assembly independent of catalytic activity in <i>C. elegans</i>.

Synapses are specialized intercellular connections where neurons transfer information, and they are funda mental for complex brain functions. Synaptic assembly is precisely regulated, and its dysfunction often leads to neurodevelopmental disorders. Previously, we demonstrated that O-GlcNAc transferase (OGT-1) is required for synaptic development in <i>C. elegans</i>. However, the underlying molecular mechanisms remain largely unknown. In this study, we found that OGT-1, the <i>C. elegans</i> homolog of mammalian OGT, regulates presynaptic assembly in AIY interneurons in a catalysis-independent manner. Mechanistically, OGT-1 acts upstream of a specific isoform of the transcription factor DAF-16/FOXO in the insulin signaling pathway. Finally, we found that OGT-1 regulates presynaptic assembly in a subset of neurons and is required for associative learning. Our findings provide insights into the role of OGT-1 in synaptic assembly.