Compartmentalized nonsense-mediated mRNA decay regulates synaptic plasticity and cognitive function via GluR1 signaling

Synaptic plasticity relies on new protein synthesis in dendrites that involves the selective translation of specific mRNAs. This requires a tight control of mRNA levels in dendrites. However, unlike the pathways that activate local mRNA translation, the mechanisms that regulate local mRNA quantity are poorly understood. Here, we show that the Nonsense-Mediated mRNA Decay (NMD) pathway locally regulates GluR1 surface levels in dendrites by modulating internalization and promoting local synthesis of GluR1. We identified AMPK as a substrate for NMD that contributes to the NMD-mediated regulation of GluR1 by limiting total GluR1 levels in dendrites. We find that neuronal ablation of NMD in adult mice attenuates learning, memory, hippocampal LTP, and potentiates perseverative/repetitive behavior. These data establish that local protein synthesis is regulated at the level of degradation in dendrites and that NMD acts locally to influence cognition and synaptic plasticity.