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  • Review Article
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Regulatory mechanisms of AMPA receptors in synaptic plasticity

Key Points

  • Learning and memory rely on activity-dependent changes in the strength of central glutamatergic synapses (synaptic plasticity). Synaptic plasticity can be bidirectional and depends on the patterning of incoming synaptic activity. Loss of synaptic plasticity causes an inability to learn.

  • AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs), together with kinetically slower NMDA (N-methyl-D-aspartate) receptors (NMDARs), are important transducers of fast synaptic transmission in glutamatergic synapses and are often the target of cellular signalling pathways responsible for regulating synaptic strength during plasticity.

  • Long-term potentiation (LTP) and long-term depression (LTD) are two important forms of bidirectional synaptic plasticity which, while different in molecular mechanisms, can coexist in the same synapse. Depending on the brain region, the origin of LTP and LTD can be presynaptic or postsynaptic.

  • In the CA1 area of the hippocampus, LTP and LTD are predominantly postsynaptic, require Ca2+ influx through NMDARs and are associated with changes in properties and trafficking of synaptic AMPARs.

  • Hippocampal LTP is complex in nature and represents an interaction of different signalling components, including kinases and phosphatases, scaffolding proteins, AMPARs and receptor-interacting proteins, cytoskeletal proteins and local dendritic protein synthesis. These signalling and structural components are functionally interconnected.

  • AMPARs can be composed of several subunits in different brain regions and during different stages of development. In the mature brain, glutamate receptor 2 (GluR2) subunits have a particularly crucial role in determining many functional properties of AMPARs.

  • Subunit composition of synaptic AMPARs regarding GluR2-lacking or GluR2-containing AMPARs can be dynamically altered by synaptic activity and substantially contribute to synaptic strength during different forms of postsynaptic plasticity.

  • Phosphorylation of AMPARs in their C-termini is crucial for the properties of these receptors and their trafficking to synapses.

  • Translocation of signalling molecules, especially calcium/calmodulin-dependent protein kinase II (CaMKII), to active synapses has an essential role in their activity-dependent strengthening during hippocampal LTP.

  • Small G-proteins are critically involved in trafficking of AMPARs and in structural reorganization of synaptic spines associated with plasticity. CaMKs could have a key role in coupling Ca2+ influxes to the activity of small G-proteins.

  • Local dendritic protein synthesis is controlled by synaptic activity in different forms of synaptic plasticity. For example, the GluR1 subunit of AMPARs can be synthesized in the dendritic shaft and spines, and contributes to changes in properties of synaptic AMPARs during LTP and homeostatic synaptic plasticity.

Abstract

Activity-dependent changes in the strength of excitatory synapses are a cellular mechanism for the plasticity of neuronal networks that is widely recognized to underlie cognitive functions such as learning and memory. AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid)-type glutamate receptors (AMPARs) are the main transducers of rapid excitatory transmission in the mammalian CNS, and recent discoveries indicate that the mechanisms which regulate AMPARs are more complex than previously thought. This review focuses on recent evidence that alterations to AMPAR functional properties are coupled to their trafficking, cytoskeletal dynamics and local protein synthesis. These relationships offer new insights into the regulation of AMPARs and synaptic strength by cellular signalling.

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Figure 1: Basic mechanisms for postsynaptic plasticity at hippocampal CA1 synapses.
Figure 2: Multistep trafficking of AMPARs to synapses.
Figure 3: Cytoskeletal dynamics and AMPAR trafficking to synapses during LTP.
Figure 4: Activity-dependent spine and dendritic protein synthesis enhances synaptic strength maintenance.

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Acknowledgements

We thank L. Vaskalis for the exceptional original art work. The authors' work on AMPARs is supported by a US National Institutes of Health grant to T.R.S. and V.A.D.

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Glossary

Rectification

The property whereby current through a channel does not flow with the same ease from the inside as from the outside. In inward rectification, for example, current flows more easily into the cell than out of the cell through the same population of channels.

Open probability

The probability that a channel will open when it is fully bound by an agonist.

Long-term depression

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

Long-term potentiation

(LTP). The prolonged strengthening of synaptic communication induced by patterned input, which is thought to be involved in learning and memory formation.

Early phase LTP

(E-LTP). The first 60–90 minutes of synaptic potentiation that does not require gene transcription. This phase is thought to be mediated primarily by protein phosphorylation and by the delivery of new receptors to the postsynaptic sites.

Excitotoxicity

Cellular toxicity involving the excessive activation of glutamate receptors in the CNS by high concentrations of glutamate or by neurotoxins, leading to cell death.

Depotentiation

Reversal of long-term potentiation by low-frequency synaptic stimulation. Depotentiation shares some characteristics with long-term depression; both are induced by low-frequency stimulation, and both require NMDA (N-methyl-D-aspartate) receptor and protein phosphatase activity. However, it is unclear whether they represent the same phenomenon or are fundamentally different.

Postsynaptic density

(PSD). An electron-dense thickening underneath the postsynaptic membrane at excitatory synapses that contains neurotransmitter receptors, structural proteins linked to the actin cytoskeleton and signalling proteins, such as kinases and phosphatases.

Caged calcium

Calcium ions bound with a high affinity to a molecular compound with multiple negative charges. Bound calcium ions can be rapidly released by a specific wavelength of light, replicating the physiological release of calcium from internal calcium stores.

PDZ domain

An amino acid sequence in proteins that binds specific sequences in the carboxyl termini of other proteins and is involved in the formation of multiprotein complexes. These complexes are important for the organization of membrane proteins, particularly at synapses.

Receptor trafficking

Alteration of the number or distribution of receptors on the cell surface, by endocytosis of existing surface receptors, recruitment to the surface of receptors from an intracellular source, lateral diffusion and clustering.

Late-phase LTP

(L-LTP). Long-term potentiation that persists beyond 60–90 minutes. L-LTP is dependent on new gene transcription and mRNA translation, leading to the stabilization of existing synapses and the formation of new synapses.

Polyribosomes

A cluster of ribosomes actively expressing new proteins on a strand of mRNA.

Homeostatic synaptic scaling

A phenomenon of synaptic strengthening in response to prolonged (hours or days) inactivity of a neuronal network.

Miniature excitatory postsynaptic current

(mEPSC). Excitatory postsynaptic currents observed in the absence of presynaptic action potentials. mEPSCs are thought to represent the postsynaptic response elicited by spontaneous presynaptic release of a single vesicle of transmitter.

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Derkach, V., Oh, M., Guire, E. et al. Regulatory mechanisms of AMPA receptors in synaptic plasticity. Nat Rev Neurosci 8, 101–113 (2007). https://doi.org/10.1038/nrn2055

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