Elsevier

Neuroscience

Volume 158, Issue 1, 12 January 2009, Pages 105-125
Neuroscience

Synaptic Plasticity
Review
Regulation of AMPA receptors and synaptic plasticity

https://doi.org/10.1016/j.neuroscience.2008.02.037Get rights and content

Abstract

Neuronal activity controls the strength of excitatory synapses by mechanisms that include changes in the postsynaptic responses mediated by AMPA receptors. These receptors account for most fast responses at excitatory synapses of the CNS, and their activity is regulated by various signaling pathways which control the electrophysiological properties of AMPA receptors and their interaction with numerous intracellular regulatory proteins. AMPA receptor phosphorylation/dephosphorylation and interaction with other proteins control their recycling and localization to defined postsynaptic sites, thereby regulating the strength of the synapse. This review focuses on recent advances in the understanding of the molecular mechanisms of regulation of AMPA receptors, and the implications in synaptic plasticity.

Section snippets

Expression of AMPARs

AMPARs consist of four closely related genes, with about 70% sequence homology (Collingridge et al., 2004), that encode the four subunits GluR1-4 or A–D (Laube et al 1998, Mano and Teichberg 1998, Rosenmund et al 1998). In situ hybridization studies, receptor autoradiography using [3H]AMPA and [3H]glutamate as ligands, and immunocytochemistry with antibodies raised against GluR1–GluR4 subunits [reviewed in (Hollmann and Heinemann 1994, Petralia et al 1999)] showed a widespread distribution of

AMPAR structure and diversity

AMPARs are largely Ca2+-impermeable, display exceptionally fast kinetics and mediate moment-to-moment synaptic signaling (Jonas, 2000). These characteristic functional properties depend on the subunit composition and on subunit modifications introduced by alternative splicing.

The AMPAR GluR1–GluR4 subunits combine in tetramers in different stoichiometries (Hollmann and Heinemann, 1994), which determine channel function (i.e. desensitization/resensitization kinetics and conductance properties) (

AMPAR post-translational modifications

Phosphorylation is a key post-translational modification in regulating AMPAR function (Carvalho et al., 2000). It can regulate the physiological properties of the channel as well as protein trafficking (Fig. 2). GluR1 subunit has been described to be phosphorylated at three serine residues located in the intracellular C-terminus: serine 831 (Ser831) can be phosphorylated by both protein kinase C (PKC) (Roche et al., 1996) and CaMKII (Mammen et al., 1997); serine 845 (Ser845) is a protein kinase

AMPAR biosynthesis and AMPAR interaction partners

AMPAR subunits are synthesized and assembled in the rough endoplasmic reticulum (ER) and then inserted into the plasma membrane after crossing the Golgi apparatus. The assembly of AMPARs in the ER and subsequent ER exit is influenced by subunit-specific interactions and RNA editing of GluR2 at the Q/R site (Greger and Esteban, 2007). GluR2 is a critical subunit in determining mammalian AMPAR function. Most mature GluR2 protein contains an arginine residue (R) within the re-entrant M2 membrane

AMPAR phosphorylation and trafficking in synaptic plasticity

AMPARs play a key role in the expression of LTP and LTD, which are extensively investigated forms of synaptic plasticity, thought to underlie learning and memory formation (Martin et al 2000, Morris 2006). LTP is characterized by a persistent increase in the efficacy of synaptic transmission, following a short period of high-frequency synaptic stimulation [e.g. (Morris, 2006)]. Pharmacological stimulation of excitatory synapses also induces a long-term increase in synaptic activity, named

AMPARs in homeostatic plasticity

Homeostatic synaptic scaling complements the Hebbian forms of plasticity (LTP and LTD), stabilizing the activity of a neuron by scaling up or down the strength of all synapses, proportionally to their initial strength (Turrigiano, 2007). Without any stabilizing mechanisms, LTP and LTD would lead neuronal activity to excessive excitation or to quiescence, respectively. Synaptic scaling provides the negative feedback to maintain neuronal activity within a functional range.

This form of plasticity

Conclusion

The recent advances in the study of the molecular mechanisms of regulation of AMPARs have contributed, to a great extent, to the understanding of synaptic plasticity. Future studies concerning the signaling mechanisms governing AMPAR trafficking, the direct/indirect interaction of AMPAR subunits with intracellular proteins, and the spatial distribution of the receptor trafficking will contribute to a better understanding of LTP and LTD. In particular, the recent development of molecular imaging

Acknowledgments

The work in the authors' laboratories is funded by Fundação para a Ciência e a Tecnologia and FEDER, Portugal (POCTI/BCI/46466/2002; POCI/SAU-NEU/58955/2004; PTDC/SAU-FCF/72283/2006).

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