Core-N-glycans are atypically abundant at the neuronal surface and regulate glutamate receptor signaling

Neurotransmitter receptors, like most surface proteins, are extensively modified by covalent addition of N-glycans during their synthesis. Surprisingly, the most abundant N-glycans in the mammalian brain are core-glycans, sugars that typically earmark immature intracellular proteins in non-neuronal cells. The function of these glycans in neurons is yet largely unknown. To address this, we combined conditional gene knockout, mass spectrometry, quantitative imaging and electrophysiological recordings in cultured neurons and brain slices. We show that core-glycans are expressed at high levels at the neuronal surface, indicating expression on functional proteins. Focusing on excitatory synapses, we found that core-glycans reduce dendritic spine density and synaptic AMPA receptor expression but are overall sufficient to sustain functional synapses. Our results indicate that core-glycans slow the desensitization of AMPA receptor complexes and reduce NMDA receptor signaling at synapses. Core-glycans hence impair NMDA receptor-dependent synaptic plasticity, unraveling a previously unrecognized role for N-glycosylation in regulating synaptic composition and transmission efficacy.