Changes in the properties and post-synaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1-4 subunits, subunit specific protein interactors, auxiliary subunits, and post-translational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose “the AMPAR code” as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity which can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling-up, or removed during LTD/homeostatic scaling-down.

Sleep is an essential process that supports learning and memory by acting on synapses through poorly understood molecular mechanisms. Using biochemistry, proteomics, and imaging in mice, we find that during sleep, synapses undergo widespread alterations in composition and signaling, including weakening of synapses through removal and dephosphorylation of synaptic AMPA-type glutamate receptors. These changes are driven by the immediate early gene Homer1a and signaling from group I metabotropic glutamate receptors mGluR1/5. Homer1a serves as a molecular integrator of arousal and sleep need via the wake- and sleep-promoting neuromodulators, noradrenaline and adenosine, respectively. Our data suggest that homeostatic scaling-down, a global form of synaptic plasticity, is active during sleep to remodel synapses and participates in the consolidation of contextual memory.

Summary Bidirectional synaptic plasticity occurs locally at individual synapses during LTP or LTD, or globally during homeostatic scaling. LTP, LTD, and homeostatic scaling alter synaptic strength through changes in post-synaptic AMPARs, suggesting the existence of overlapping molecular mechanisms. Phosphorylation is critical for controlling AMPAR trafficking during LTP/LTD. Here we addressed the role of AMPAR phosphorylation during homeostatic scaling. We observed bidirectional changes of the levels of phosphorylated GluA1 S845, during scaling, resulting from a loss of PKA from synapses during scaling-down and enhanced activity of PKA in synapses during scaling-up. Altered synaptic PKA signaling, requiring the scaffold AKAP5, alters the effectiveness of neuromodulators and NMDAR activation. Increased phosphorylation of S845 drove scaling-up while a knock-in mutation of S845 blocked scaling-up. Finally we show that AMPARs scale differentially based on their phosphorylation status at S845. These results show that rearrangement in PKA signaling controls AMPAR phosphorylation and surface targeting during homeostatic plasticity.