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  • Review Article
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The role of receptor diffusion in the organization of the postsynaptic membrane

Key Points

  • The structure of the postsynaptic membrane is highly heterogeneous and dynamic. Receptors are stabilized by a network that consists of scaffold proteins, adhesion proteins and the cytoskeleton, and changes in the receptor profile of the membrane are mediated by endocytosis, exocytosis and diffusion.

  • Receptor diffusion has a role during the formation of new synapses, and during synaptic turnover and synaptic plasticity. There are five main categories of diffusion, ranging from 'free' to 'confined'. The subsynaptic scaffold network constitutes a barrier to receptor movement, resulting in confined diffusion.

  • Techniques such as single particle tracking and fluorescence recovery after photobleaching have been used to follow receptor movements. Fast random movements are interspersed with periods of relative immobility, indicating the presence of transient submicrometre domains in the membrane that are separated by barriers. Within these domains, receptor diffusion is as fast as expected from theoretical calculations. Receptors can escape these 'corrals' by 'jumping the fence' or by passing through gaps when the membrane skeleton is transiently dissociated.

  • Receptors can diffuse individually or as part of a cluster. Clusters are aggregations of receptors that are stabilized by their associations with scaffold components. Diffusion of cluster-associated receptors may be due to movement of the entire cluster or movement of the individual receptor within the cluster.

  • Equilibrium between receptors entering and exiting subdomains (corrals) accounts for the apparent stability of the postsynaptic membrane. So, gross changes in receptor number during synaptogenesis and synaptic plasticity can be considered to result from a change in the set-point of this equilibrium.

Abstract

Neurotransmitter receptor movement into and out of synapses is one of the core mechanisms for rapidly changing the number of functional receptors during synaptic plasticity. Recent data have shown that rapid gain and loss of receptors from synaptic sites are accounted for by endocytosis and exocytosis, as well as by lateral diffusion of receptors in the plane of the membrane. These events are interdependent and are regulated by neuronal activity and interactions with scaffolding proteins. Here we focus on the physical laws that govern receptor diffusion and stabilization, and how this might reshape how we think about the specific regulation of receptor accumulation at synapses.

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Figure 1: Schematic representation of the structural organization of a generic excitatory glutamatergic synapse.
Figure 2: Hypothetical diagram of the arrangements of gephyrin molecules and glycine receptors (GlyRs) at inhibitory synapses.
Figure 3: Schematic representation of the compartmentalization of protein movements in plasma membranes.
Figure 4: Receptor diffusion in neurons measured by single particle tracking.
Figure 5: Kinetic diagram of dynamic instability and equilibrium of the receptor–scaffold complex.
Figure 6: Immobilization of AMPAR by calcium influx.
Figure 7: Receptor exchanges between synaptic, extrasynaptic and intracellular compartments are regulated by confinement.

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Acknowledgements

The work of A.T. and D.C. presented in this review has been supported by the CNRS (Centre National de la Recherche Scientifique), INSERM (Institut National de la Santé et de la Recherche Médicale), FRM (Fondation pour la Recherche Médicale), Conseil Régional d'Aquitaine, AFM (Association Française contre les Myopathies) and IRME (Institut de Recherche sur la Moelle Epinière). We thank C. Vannier and L. Cognet for their precious comments on the manuscript, and the members of A.T. and D.C. laboratories involved in this work.

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DATABASES

Swiss-Prot

Cadherin

β-catenin

CaMKII

Dlc1

Dlc2

ephrin-B receptor

GABARAP

Gephyrin

GKAP

GRIP

Homer

Neurexin

Neuroligin

PICK

PSD-95/SAP90

Raft1

Shank

Sidekick

Glossary

SUPRAMOLECULAR MACHINE

A regulated assembly of chemically connected molecules performing a given function.

LONG-TERM DEPRESSION

(LTD). An enduring weakening of synaptic strength that is thought to participate, together with long-term potentiation (LTP), in cellular mechanisms of learning and memory in structures such as the hippocampus and cerebellum. Unlike LTP, which is produced by brief high-frequency stimulation, LTD can be produced by long-term, low-frequency stimulation.

SILENT SYNAPSE

A synapse that contains NMDA receptors but no AMPA receptors and is therefore functionally silent during low-frequency, basal synaptic transmission.

PERIJUNCTIONAL MEMBRANE

The surface area of postsynaptic membrane that surrounds a synaptic complex.

CLATHRIN

A major structural component of coated vesicles that are implicated in protein transport.

LONG-TERM POTENTIATION

(LTP). An enduring increase in the amplitude of excitatory postsynaptic potentials as a result of high-frequency (tetanic) stimulation of afferent pathways. It is measured both as the amplitude of excitatory postsynaptic potentials and as the magnitude of the postsynaptic-cell population spike. LTP is most often studied in the hippocampus and is considered to be the cellular basis of learning and memory in vertebrates.

PALMITOYLATION

Covalent attachment of a palmitate (16-carbon saturated fatty acid) to a cysteine residue through a thioester bond.

ANISOTROPIC

A medium in which physical properties have different values when measured along axes orientated in different directions.

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Choquet, D., Triller, A. The role of receptor diffusion in the organization of the postsynaptic membrane. Nat Rev Neurosci 4, 251–265 (2003). https://doi.org/10.1038/nrn1077

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