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  • Review Article
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Synaptic AMPA receptor composition in development, plasticity and disease

Nature Reviews Neuroscience volume 17, pages 337–350 (2016)Cite this article

Subjects

Key Points

  • AMPA receptors (AMPARs) mediate nearly all fast excitatory neurotransmission in the mammalian CNS.

  • AMPARs are heteromeric assemblies of four core subunits, GluA1–4, together with auxiliary subunits and a dynamically changing set of interacting proteins.

  • The assembly and subunit composition of AMPARs undergo activity-dependent regulation during biogenesis.

  • The presence or absence of the edited form of the GluA2 subunit, GluA2(R), determines whether the assembled AMPAR gates Ca2+.

  • There is a wealth of evidence suggesting that the synaptic trafficking, retention and removal of AMPARs of specific subunit combinations and that have specific biophysical properties are of paramount importance for synaptic plasticity. These AMPAR-subtype-specific events are regulated both by protein interactions and by phosphorylation events within the carboxy-terminal tails.

  • Recent studies reporting that the C-terminal tails are not essential for plasticity and that very few GluA1 subunits are phosphorylated have prompted a major re-evaluation of the fundamental mechanisms of AMPAR trafficking and synaptic plasticity.

  • Understanding the molecular details of AMPAR assembly, trafficking, recycling and degradation, and how dysfunction affects synapses, neurons and networks will provide invaluable insights into neurological and neurodegenerative disease.

Abstract

AMPA receptors (AMPARs) are assemblies of four core subunits, GluA1–4, that mediate most fast excitatory neurotransmission. The component subunits determine the functional properties of AMPARs, and the prevailing view is that the subunit composition also determines AMPAR trafficking, which is dynamically regulated during development, synaptic plasticity and in response to neuronal stress in disease. Recently, the subunit dependence of AMPAR trafficking has been questioned, leading to a reappraisal of this field. In this Review, we discuss what is known, uncertain, conjectured and unknown about the roles of the individual subunits, and how they affect AMPAR assembly, trafficking and function under both normal and pathological conditions.

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Figure 1: AMPAR receptor topology and properties.
Figure 2: The slot hypothesis of LTP.
Figure 3: Subunit-specific AMPAR trafficking through the secretory pathway.
Figure 4: CP-AMPAR trafficking in hippocampal plasticity.
Figure 5: CP-AMPAR plasticity at cerebellar granule cell–stellate cell synapses.

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Acknowledgements

The authors are grateful to the UK Medical Research Council (MRC), BBSRC, Alzheimer's Society, BRACE and British Heart Foundation for financial support. They thank A. Evans and R. Carmichael for critical reading and constructive suggestions.

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  1. School of Biochemistry, Centre for Synaptic Plasticity, Biomedical Sciences Building, University of Bristol, Bristol, BS8 1TD, UK

    Jeremy M. Henley & Kevin A. Wilkinson

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Glossary

Ionotropic glutamate receptors

A family of glutamate-gated cation channels that can be subdivided into AMPA, NMDA and kainate receptors on the basis of their pharmacological properties.

Synaptic plasticity

The process by which synaptic transmission can strengthen or weaken in response to specific patterns of activity.

PDZ domain

A structural domain of 80–90 amino acids that binds cognate proteins containing a short carboxy-terminal PDZ ligand. Among other functions, PDZ interactions anchor receptor proteins in the membrane to cytoskeletal components.

Long-term potentiation

(LTP). The persistent strengthening of synaptic transmission that is mainly due to increased numbers of postsynaptic AMPA receptors.

Long-term depression

(LTD). A long-lasting decrease in synaptic strength that is mainly due to reduced numbers of postsynaptic AMPA receptors.

Membrane-associated guanylate kinase

(MAGUK). A superfamily of multidomain, catalytically inert scaffolding proteins that facilitate interactions between cytoskeletal proteins, microtubule- or actin-based machinery and molecules involved in signal transduction.

Auxiliary subunits

Specialized transmembrane components of the AMPA receptor complex that modulate forward trafficking and the pharmacological and functional properties of the surface-expressed receptor.

RNA editing

A post-transcriptional modification process that changes an RNA molecule to insert, delete or substitute nucleotides. Editing of the base A→I at a specific site results in the substitution of Q with R in almost all GluA2 subunits in the CNS.

Ca2+-impermeable AMPARs

(CI-AMPA receptors). Tetrameric assemblies containing the RNA-edited form of the GluA2 subunit in which the uncharged amino acid glutamine (Q) is changed to the positively charged arginine (R) in the ion channel.

Ca2+-permeable AMPARs

(CP-AMPA receptors). AMPA receptors are calcium permeable when they lack GluA2 or contain unedited GluA2.

Homeostatic synaptic scaling

A feedback mechanism by which a neuron can upregulate or downregulate its synaptic responsiveness in response to sustained alterations in activity.

Silent synapses

Synapses that contain postsynaptic NMDA receptors but that lack AMPA receptors, rendering the synapse silent at resting membrane potential.

AKAP150

(Also known as AKAP79 in humans). A specialized scaffold protein that can bring together protein kinase A (PKA), PKC, the scaffolding proteins synapse-associated protein 97 (SAP97) and postsynaptic density protein 95 (PSD95) and the Ca2+-dependent protein phosphatase calcineurin with AMPA receptors at synapses.

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Henley, J., Wilkinson, K. Synaptic AMPA receptor composition in development, plasticity and disease. Nat Rev Neurosci 17, 337–350 (2016). https://doi.org/10.1038/nrn.2016.37

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