Posttranslational modifications of AMPA receptors in synaptic function and memory

AMPA receptors, members of the ionotropic glutamate receptor family, are the principal mediators of fast excitatory synaptic transmission in the brain, and their trafficking to and from synapses is critical for neuronal communication. AMPA receptor trafficking is primarily regulated by posttranslational modifications. These receptors undergo diverse site-specific posttranslational modifications, including phosphorylation, palmitoylation, ubiquitination, S-nitrosylation, N-glycosylation, O-GlcNAcylation, and SUMOylation. Crosstalk among these modifications further adds to the complexity of AMPA receptor regulation. Accumulating evidence indicates that posttranslational modifications not only govern receptor trafficking and synaptic retention but also regulate synaptic strength during both Hebbian and non-Hebbian forms of synaptic plasticity, as well as memory function. Long-term potentiation induces site-specific modifications that promote synaptic incorporation of AMPA receptors, whereas long-term depression is associated with modifications that drive receptor internalization. Mutations affecting posttranslational modification sites disrupt AMPA receptor trafficking, impair synaptic plasticity, and alter memory function. Moreover, aberrant regulation of AMPA receptor posttranslational modifications has been linked to memory dysfunction during aging and in several neurological disorders. This review summarizes current understanding of how posttranslational modifications of AMPA receptors regulate synaptic plasticity, contribute to memory function, and are implicated in cognitive decline in aging and in disorders such as Alzheimer's disease and schizophrenia.