Interplay between NMDA receptor dynamics and the synaptic proteasome

Proteasome activity at the excitatory synapse plays an important role in neuronal communication. The proteasome translocation to synapses is mediated by neuronal activity, in particular the activation of N‐methyl‐d‐aspartate receptors (NMDARs). These receptors are composed of different subunits with distinct trafficking properties that provide various signalling and plasticity features to the synapse. Yet whether the interplay between the proteasome and NMDAR relies on specific subunit properties remain unclear. Using a combination of single molecule and immunocytochemistry imaging approaches in rat hippocampal neurons, we unveil a specific interplay between GluN2B‐containing NMDARs (GluN2B‐NMDARs) and the synaptic proteasome. Sustained proteasome activation specifically increases GluN2B‐NMDAR (not GluN2A‐NMDAR) lateral diffusion. In addition, when GluN2B‐NMDAR expression is downregulated, the proteasome localization decreases at glutamatergic synapses. Collectively, our data fuel a model in which the cellular dynamics and location of GluN2B‐NMDARs and proteasome are intermingled, shedding new lights on the NMDAR‐dependent regulation of synaptic adaptation. We unveil a specific interplay between the proteasome and GluN2B‐containing NMDA receptors. We show that sustained proteasome activation increases these receptors' lateral diffusion, and their downregulation decreases the proteasome synaptic localization.