FXR1P Limits Long-Term Memory, Long-Lasting Synaptic Potentiation, and De Novo GluA2 Translation

Translational control of mRNAs allows for rapid and selective changes in synaptic protein expression that are required for long-lasting plasticity and memory formation in the brain. Fragile X Related Protein 1 (FXR1P) is an RNA-binding protein that controls mRNA translation in nonneuronal cells and colocalizes with translational machinery in neurons. However, its neuronal mRNA targets and role in the brain are unknown. Here, we demonstrate that removal of FXR1P from the forebrain of postnatal mice selectively enhances long-term storage of spatial memories, hippocampal late-phase long-term potentiation (L-LTP), and de novo GluA2 synthesis. Furthermore, FXR1P binds specifically to the 5′ UTR of GluA2 mRNA to repress translation and limit the amount of GluA2 that is incorporated at potentiated synapses. This study uncovers a mechanism for regulating long-lasting synaptic plasticity and spatial memory formation and reveals an unexpected divergent role of FXR1P among Fragile X proteins in brain plasticity. [Display omitted] •Removal of FXR1P increases protein synthesis-dependent L-LTP and memory storage•FXR1P limits GluA2 synthesis and its activity-dependent synaptic delivery•FXR1P represses GluA2 mRNA translation via a GU-rich element in its 5′ UTR•Fragile X proteins have divergent roles in synaptic plasticity and memory storage Control over protein synthesis is important for long-lasting plasticity and memory storage in the brain. Cook, Nuro, et al. now reveal that the RNA-binding protein FXR1P acts as a molecular brake that limits synthesis and synaptic incorporation of the AMPAR subunit GluA2, ultimately constraining long-term plasticity and memory formation.