Lateral organization of the postsynaptic density

Abstract

Fast excitatory synaptic transmission is mediated by AMPA-type glutamate receptors (AMPARs). It is widely accepted that the number of AMPARs in the postsynaptic density (PSD) critically determines the efficiency of synaptic transmission, but an unappreciated aspect of synapse organization is the lateral positioning of AMPARs within the PSD, that is, their distribution across the face of a single synapse. Receptor lateral positioning is important in a number of processes, most notably because alignment with presynaptic release sites heavily influences the probability of receptor activation. In this review, we summarize current understanding of the mechanisms that dynamically control the subsynaptic positioning of AMPARs. This field is still at early stages, but the recent wave of developments in super-resolution microscopy, synapse tomography, and computational modeling now enable the study of lateral protein distribution and dynamics within the nanometer-scale boundaries of the PSD. We discuss data available measuring the lateral distribution of glutamate receptors and scaffold proteins within the PSD, and discuss potential mechanisms that might give rise to these patterns. Elucidating the mechanisms that underlie the lateral organization of the PSD will be critical to improve our understanding of synaptic processes whose disruption may be unexpectedly important in neurological disorders. This article is part of a Special Issue entitled Membrane Trafficking and Cytoskeletal Dynamics in 'Neuronal Function'.

Figure 1

(A) Side-view of a synapse where a single release event activates all postsynaptic AMPARs (green), which are shown as randomly positioned. Vertical arrows indicate opened channels. Release from sites anywhere in the presynaptic active zone will elicit EPSCs (below) with little variance. (B) A synapse for which a single release event activates only a subset of randomly positioned receptors. A release event in the center of the synapse (in red) is likely to activate more receptors and trigger a more robust postsynaptic current than a release site located more peripherally (blue). (C) In contrast, if postsynaptic AMPARs distribution is not random, the local density of receptors at the release sites, not simply their number, will determine the amplitude of the EPSC elicited by a release event. Glutamate release aligned with a receptor-sparse region (red), will trigger a smaller EPSC than release aligned with denser region of the synapse (blue). Modulating the alignment of presynaptic release machinery with postsynaptic AMPARs, potentially via transsynaptic mechanisms involving the receptors themselves, is thus a potential mechanism to decrease (D) or increase (E) synaptic strength.

Figure 2

A scheme outlining different mechanisms that can control glutamate receptor positioning, as discussed in this review.

Figure 3. Two classes of mechanisms that may control AMPAR positioning in the synapse

(A) Side view of a synapse, showing hetero-oligomeric scaffold modules controlling the position of AMPARs by direct protein-protein interactions. In the binding model, AMPAR/TARP complexes are stably anchored by interacting with MAGUK proteins such as PSD-95. The multimeric MAGUK proteins and other scaffold molecules can engage in multiple interactions with each other, and can assemble into hetero-oligomeric scaffold modules. PSD-95 forms complexes with GKAP and Shank molecules that interact with the actin cytoskeleton via cortactin and other intermediates. Intramolecular interactions between the SH3 and GK domains of MAGUKs potentially control oligomerization of numerous components of scaffold modules, as well as signaling molecules (not shown). Drawings are not to scale. (B) Top view of a synapse, showing hetero-oligomeric scaffold modules organizing the lateral distribution of AMPARs in the synapse. Modification of the binding competency of scaffolding molecules can change their oligomerization capability (light vs. dark blue small circles) and regulate interactions with AMPARs over time. (C) Side view of a synapse, showing different sources of macromolecular crowding. Scaffolding molecules close to the membrane can reduce AMPAR mobility, even if binding to receptors is rare. Postsynaptic transmembrane proteins such as neuroligin and cadherins may serve as obstacles to receptor motion, or alternatively may form structures more reminiscent of fences that subdivide the PSD. Transmembrane or extracellular proteins contribute to macromolecular crowding in the synaptic cleft, where the bulky extracellular domain of the AMPAR may increase obstruction of receptor motion. (D) Macromolecular crowding by various proteins (small circles) as in C can retain receptors within the synapse and within synapse subdomains over time. Note that the same distribution of receptors as in B could be produced by a differential distribution of obstructions. Both mechanisms shown in B and D, macromolecular crowding and binding to hetero-oligomeric scaffold modules, likely operate in tandem to determine receptor lateral distribution.