O-GlcNAcase contributes to cognitive function in Drosophila

Abstract

<i>O</i>-GlcNAcylation is an abundant post-translational modification in neurons. In mice, an increase in <i>O</i>-GlcNAcylation leads to defects in hippocampal synaptic plasticity and learning. <i>O</i>-GlcNAcylation is established by two opposing enzymes: <i>O</i>-GlcNAc transferase (OGT) and <i>O</i>-GlcNAcase (OGA). To investigate the role of OGA in elementary learning, we generated catalytically inactive and precise knockout <i>Oga</i> alleles (<i>Oga^D133N</i> and <i>Oga^KO</i> , respectively) in <i>Drosophila melanogaster</i> Adult <i>Oga^D133N</i> and <i>Oga^KO</i> flies lacking <i>O</i>-GlcNAcase activity showed locomotor phenotypes. Importantly, both <i>Oga</i> lines exhibited deficits in habituation, an evolutionarily conserved form of learning, highlighting that the requirement for <i>O</i>-GlcNAcase activity for cognitive function is preserved across species. Loss of <i>O</i>-GlcNAcase affected a number of synaptic boutons at the axon terminals of larval neuromuscular junction. Taken together, we report behavioral and neurodevelopmental phenotypes associated with <i>Oga</i> alleles and show that Oga contributes to cognition and synaptic morphology in <i>Drosophila</i>.