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Receptor trafficking and synaptic plasticity

Nature Reviews Neuroscience volume 5, pages 952–962 (2004)Cite this article

Key Points

  • Synaptic plasticity is the basis of information storage in the brain. Two of the most studied forms of plasticity, long-term potentiation (LTP) and long-term depression (LTD), involve both glutamate and GABA (γ-aminobutyric acid) receptors, and it is becoming clear that the trafficking of these receptors is an important mechanism in both LTP and LTD.

  • Postsynaptic changes in AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid) receptors (AMPARs) are thought to be important for the expression of LTP. This could involve either the modulation of AMPARs at the synapse or the rapid recruitment of new AMPARs to the synapse. LTD might occur through a mirror mechanism or a distinct process. There is strong evidence that both LTP and LTD involve changes in the number of AMPARs at the synapse.

  • AMPARs can enter or leave the synapse through exocytosis and endocytosis or through lateral diffusion within the membrane. Various protein kinases and phosphatases have been implicated in these processes. In addition, proteins that bind to AMPARs and regulate their function have also been identified. These include N-ethylmaleimide-sensitive factor (NSF) and the PDZ-domain-containing proteins postsynaptic density protein 95 (PSD-95), AMPAR-binding protein (ABP), glutamate-receptor interacting protein (GRIP) and protein interacting with C-kinase (PICK).

  • NMDA (N-methyl-D-aspartate) receptors (NMDARs) are the most important known trigger for long-term synaptic plasticity. They also show considerable mobility within the membrane and between intracellular and extracellular compartments of cells, although these processes are less well understood than for AMPARs. There is evidence that such trafficking is regulated by activity and could be a mechanism for metaplasticity.

  • Kainate receptors are also important for synaptic plasticity, but little is known about the regulation of their trafficking. Furthermore, the G-protein-coupled metabotropic glutamate receptors (mGluRs) bind to various proteins that could regulate their trafficking in response to activity.

  • Ionotropic GABAARs help to regulate the activation of NMDARs, and transmission that is mediated by GABAARs is also modulated in response to activity. Their trafficking is likely to be important for synaptic plasticity, and this process shows some similarities to trafficking of AMPARs. Several proteins that bind GABAARs and could regulate their trafficking in response to activity have been identified.

  • Metabotropic GABABRs are also important for plasticity, and several proteins have been identified that bind these receptors, but their functional importance is unclear.

  • Some common principles are emerging in the regulation of receptor trafficking during synaptic plasticity. These include the stabilization of receptors at the membrane by scaffolding proteins and regulation by kinases and phosphatases. However, specific receptors or subunits are also trafficked by selective mechanisms.

Abstract

Long-term potentiation and long-term depression are processes that have been widely studied to understand the molecular basis of information storage in the brain. Glutamate receptors are required for the induction and expression of these forms of plasticity, and GABA (γ-aminobutyric acid) receptors are involved in their modulation. Recent insights into how these receptors are rapidly moved into and out of synaptic membranes has profound implications for our understanding of the mechanisms of long-term potentiation and long-term depression.

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Figure 1: Synaptic plasticity in the hippocampus and glutamate receptor subtypes.
Figure 2: Rapid trafficking of AMPARs during synaptic plasticity.
Figure 3: Proteins that associate with the C termini of AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor) (a) or GABAAR (type A γ-aminobutyric acid receptor) (b) subunits.

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Acknowledgements

Authors are listed in alphabetical order. Supported by the Medical Research Council, Wellcome Trust, CIHR and National Instititutes of Health. G.L.C. is a Royal Society–Wolfson Merit Award Holder. Y.T.W. is a HHMI international scholar. Thanks to A. Doherty for advice.

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Authors and Affiliations

  1. Department of Anatomy, MRC Centre for Synaptic Plasticity, School of Medical Sciences, University Walk, Bristol, BS8 1TD, UK

    Graham L. Collingridge & John T. R. Isaac

  2. Brain Research Center and Department of Medicine, Vancouver Hospital and Health Sciences Center, University of British Columbia, Vancouver, V6T 1Z3, Canada

    Graham L. Collingridge & Yu Tian Wang

  3. National Institutes of Health, 37 Convent Drive, Building 35/Room 3C-1002, MSC 3701, Bethesda, 20892-3701, Maryland, USA

    John T. R. Isaac

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Correspondence to Graham L. Collingridge.

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DATABASES

Entrez Gene

AKAP150

BDNF

CaMKII

GluR1

Homer1

NSF

PSD-95

SAP97

FURTHER INFORMATION

Encyclopedia of Life Sciences

AMPA receptors

GABAA receptors

GABAB receptors

Glutamate as a neurotransmitter

Glutamatergic synapses: molecular organisation

NMDA receptors 

Collingridge's research

Isaac's research

Wang's research

Glossary

BANDS 4.1N AND 4.1G

These are members of the Band 4.1 family of proteins that are thought to help stabilize the sub-membranous anchoring network through interactions with spectrin, actin and various ion channels and receptors.

PDZ DOMAIN

A peptide-binding domain that is important for the organization of membrane proteins, particularly at cell–cell junctions, including synapses. It can bind to the carboxyl termini of proteins or can form dimers with other PDZ domains. PDZ domains are named after the proteins in which these sequence motifs were originally identified (PSD-95, discs large, zona occludens 1).

UBIQUITINATION

The attachment of the protein ubiquitin to lysine residues of other molecules, often as a tag for their rapid cellular degradation.

PALMITOYLATION

Protein palmitoylation is a common protein modification in which a 16-carbon-atom saturated fatty acid (palmitate) is covalently attached to a cysteine residue through a thioester bond.

RAS PROTEINS

A group of small GTPases involved in growth, differentiation and cellular signalling that require the binding of GTP to enter into their active state.

KINDLING

A model of epilepsy in which repeated electrical or chemical stimulation of limbic structures, such as the amygdala or hippocampus, evokes progressively more severe electrical and behavioural responses, culminating in a generalized seizure. The kindling state is highly stable and can persist for months to years.

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Collingridge, G., Isaac, J. & Wang, Y. Receptor trafficking and synaptic plasticity. Nat Rev Neurosci 5, 952–962 (2004). https://doi.org/10.1038/nrn1556

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