The AMPA Receptor Code of Synaptic Plasticity

Abstract

Changes in the properties and postsynaptic 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-GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational 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 that 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.

Keywords: NMDA receptors; glutamate receptors; homeostatic plasticity; homeostatic scaling; learning; long-term depression; long-term potentiation; memory; synaptic plasticity.

Figure 1.

AMPAR post-translational modifications and the AMPAR code. A. Schematic of AMPAR structure. % identity indicates the identity of each domain between the GluA1-4 subunits. B. Amino acid sequences of GluA1-4 C-terminal tails with known post-translational modifications indicated. Modifications with a “?” are known to occur but the modified amino acid has not been identified. C. Schematic of known interactions between AMPAR post-translational modifications.

Figure 2.

The AMPAR hierarchy and PSD slot hypothesis. During synaptic plasticity AMPARs are added or subtracted from PSD/extracellular slots (A), which are modified in number and/or in their affinity for AMPARs during plasticity (B). Trafficking AMPARs then populate these PSD slots in a hierarchy based on their i) affinity for the PSD slots, and ii) their mobilization and mobility on the cell-surface. AMPARs enter the PSD slots through lateral diffusion from extra-synaptic pools of surface receptors. During LTP, surface pools are locally enriched with GluA1-containing AMPARs through activity-dependent exocytosis, whereas during LTD surface AMPARs are locally depleted through endocytosis of GluA2-containing receptors.

Figure 3.

Subunit-specific mechanisms of homeostatic scaling. A and B, schematics of known mechanisms of homeostatic scaling-up (A) and scaling-down (B) based on GluA1 or GluA2/3.

Figure 4.

Communication between Hebbian and homeostatic plasticity based on the AMPAR code. AMPARs are modified at synapses which have undergone Hebbian plasticity, for example phosphorylation of GluA1 during LTP. These synapses maintain signaling which sustains a population of modified receptors. During homeostatic scaling, synapses across the neuron are strengthened or weakened by adding or subtracting AMPARs respectively. This global plasticity is modified locally by the population of modified AMPARs which are either resistant or hypersensitive to homeostatic scaling. This interaction allows global homeostatic plasticity to be sensitive to previous history of Hebbian plasticity.