Tuning synaptic strength by regulation of AMPA glutamate receptor localization

Abstract

Long-term potentiation (LTP) of excitatory synapses is a leading model to explain the concept of information storage in the brain. Multiple mechanisms contribute to LTP, but central amongst them is an increased sensitivity of the postsynaptic membrane to neurotransmitter release. This sensitivity is predominantly determined by the abundance and localization of AMPA-type glutamate receptors (AMPARs). A combination of AMPAR structural data, super-resolution imaging of excitatory synapses, and an abundance of electrophysiological studies are providing an ever-clearer picture of how AMPARs are recruited and organized at synaptic junctions. Here, we review the latest insights into this process, and discuss how both cytoplasmic and extracellular receptor elements cooperate to tune the AMPAR response at the hippocampal CA1 synapse.

Keywords: AMPA receptor structure; AMPA receptor traffic; cryo‐EM; long‐term potentiation; short‐term plasticity; synaptic plasticity.

Figure 1

(A) Confocal image of GFP-expressing hippocampal pyramidal neurons in an organotypic hippocampal slice. Inset shows a zoomed in region of dendrite, imaged by STED microscopy, with a postsynaptic spine circled in white. (B) Schematic of the postsynaptic molecular changes occurring during potentiation of an excitatory glutamatergic synapse. Glutamate release from presynaptic vesicles activates postsynaptic AMPARs, which enable the influx of Na⁺ ions to depolarize the postsynaptic cell (panel 1), thereby activating NMDARs and the influx of Ca²⁺ ions (panel 2). Subsequent postsynaptic Ca²⁺ signaling processes, such as the activation of CAMKII (panel 3), result in the recruitment of further AMPARs and their organization into transsynaptic nanocolumns, as well as the growth of the postsynaptic density and protrusion of the dendritic spine.

Figure 2

(A) AMPAR structure colored by sequence conservation between the four subunits (NTD: N terminal domain, LBD: ligand-binding domain, TMD: transmembrane domain, CTD: C terminal domain). The LBD and TMD sequences are highly conserved (magenta), whilst the NTD and CTD show greater sequence diversity (cyan), enabling subunit-specific interactions. (B) Schematic of a heteromeric AMPAR on the postsynaptic membrane, held in the postsynaptic density by interactions between the associated auxiliary protein TARPγ8 and the three PDZ domains of PSD95, and the NTD that extends into the synaptic cleft. Cytosolic diversity of synaptic AMPAR complexes can arise by (i) the stoichiometry of associated TARPs (ii) TARP type, for example, different length C-tails of TARP γ2 and TARPγ8 (iii) PDZ anchoring by additional associated proteins, for example, CKAMPs. (C) Schematic depicting the subunit-specific effect of the NTD and TARPγ8 PDZ interactions on synaptic transmission. Excitatory postsynaptic current (EPSC) amplitude, normalized to a neighboring transfected neuron, is reduced when removing the TARPγ8 PDZ binding motif (γ8ΔPDZ). γ8 PDZ deletion prevents GluA1-mediated synaptic transmission, which can be partially rescued by the NTD of GluA2 (derived from Watson et al., 2021).

Figure 3

(A) Proposed model of the role of the NTD in synaptic anchoring of AMPARs. The stability of the tetrameric interface in GluA2-containing receptors (highlighted in black; ‘side view’) may enable efficient synaptic anchoring, as receptors without this interface (GluA1 homomers) or with a disrupted interface (GluA2_F231A) show reduced EPSCs following Schaffer collateral stimulation. The flexibility of the NTD with a disrupted interface has implications for both the gating and synaptic anchoring of the receptor. (B) Synaptic accumulation of AMPARs is maintained by TARP (green) PDZ interactions with PSD-95 (brown). Subsynaptic positioning into receptor clusters opposing vesicle release is influenced by both the core subunit, determining subunit-specific NTD interactions, and the associated auxiliary proteins providing PSD-95 anchoring. NTD interactions with synaptic cleft molecules may be disturbed in receptors with a broken NTD dimeric interface, making them less likely to be maintained in a stable synaptic position.