ReviewReceptor trafficking and the plasticity of excitatory synapses
Introduction
Long-term potentiation (LTP) of synaptic transmission was first described nearly 30 years ago and is thought to be a neuronal mechanism of information storage (reviewed in [1]). Here, we review recent advances that have clarified the role of receptor trafficking in LTP and the mechanisms that control the strength of excitatory synapses. In particular, we examine the roles of receptor subunit composition and synaptic activity in the delivery of channels to the synaptic membrane, and the establishment of presumptive ‘slots’ or occupancy sites. Interactions of channels with anchorage and transport proteins govern receptor trafficking; these are regulated by phosphorylation to provide activity and subunit-specificity to trafficking mechanisms.
Excitatory synapses in the central nervous system release glutamate onto two major ionotropic receptor subtypes, α-amino-3-hydroxyl-5-methyl-4-isoxazole propionate receptors (AMPARs) and N-methyl-D-aspartate receptors (NMDARs). AMPARs mediate fast excitatory transmission between neurons whereas NMDARs are key in the induction of specific forms of synaptic plasticity, including LTP and long-term depression (LTD). One major step in understanding LTP came in 1995 with the description of the ‘silent synapse’ (reviewed in [2]). Silent synapses express NMDARs but not AMPARs and are thus silent under resting conditions. Following the paired activation of both presynaptic (release of glutamate) and postsynaptic (depolarization) loci, responses from functional AMPARs are observed in formerly silent synapses, implicating the insertion of postsynaptic AMPARs in LTP. Such studies largely refocused the debate regarding the loci of LTP expression to postsynaptic sites and opened the door to further studies of the postsynaptic trafficking of AMPARs.
Section snippets
Synthesis and heteromerization of receptors
Multimeric channels such as AMPARs follow a complex pathway to the synapse, starting with subunit synthesis and assembly into receptors in the rough endoplasmic reticulum (ER), and culminating in receptor insertion in the synaptic plasma membrane (Fig. 1). AMPARs are tetramers composed of subunits GluR1–4 (GluRA–D), each with a large extracellular amino (N) terminal domain, three membrane-spanning domains, a hairpin that contributes to the pore, and a cytoplasmic carboxyl terminal domain (CTD;
Subunit-dependent AMPAR insertion
AMPAR synaptic insertion and removal are closely coupled to synaptic strengthening and depression, respectively. Recent work revealed two general mechanisms of synaptic insertion, which both depend strongly on subunit composition. The first is de novo insertion, manifest by GluR1-containing receptors and dependent upon tetanic stimulation. GluR1-containing receptors appear to act as a vanguard, entering synapses where no AMPARs resided previously, depending on synaptic activity. The second
AMPAR synaptic localization and anchoring
AMPAR subunit CTDs contribute to trafficking through subunit-specific interactions with cytosolic proteins that engage the trafficking machinery, anchor receptors at membranes, or regulate receptor–binding protein interactions. Here, we discuss some of the identified proteins that bind AMPAR subunits and most likely dictate the subunit-specificity of receptor trafficking.
Events governing AMPAR insertion
Evidently there is a vesicle (v)SNARE/target (t)SNARE interaction, akin to the one involved in presynaptic release, that occurs during AMPAR insertion into the plasma membrane, because AMPAR currents are reduced following the postsynaptic application of botulinum toxin [39], which cleaves and inactivates SNAREs, and also reduces LTP [40]. NSF may have a role in the insertion process. Presynaptically, NSF's role is to dissociate the SNARE complex helical bundle, with the aid of SNAPs (soluble
Events governing AMPAR removal
AMPARs may be removed from the active zone either directly by endocytosis or by movement within the plasma membrane away from the synapse, followed by endocytosis via a clathrin-dependent mechanism [42]. Phosphorylation may release AMPAR from anchorage proteins and initiate endocytosis. Indeed, GluR2 is phosphorylated at Ser880 by protein kinase C (PKC) [43]. In the cerebellum, stimulations that induce LTD increase GluR2 Ser880 phosphorylation, decrease its affinity for GRIP, and decrease
AMPAR recycling and degradation
After endocytosis, a receptor may traffick to an early endosome and, from there, either back to the plasma membrane or to late endosomes and lysosomes for degradation. AMPAR internalization follows these different paths, and depends on NMDAR or AMPAR activation and phosphorylation of the GluR1 CTD [52••]. Following NMDAR activation, Ser845 in the GluR1 CTD is dephosphorylated and the receptor is transported to a recycling endosome. Protein phosphatase 1, which is clustered at synapses by NMDAR
Conclusions and future directions
Changes in synaptic strength that occur following LTP or LTD induction can now be related to changes in the exocytosis and endocytosis of AMPARs. The subunit composition of the receptor, together with the prior history and the current activity of the synapse all regulate AMPAR trafficking. The assignment of specific functions to transport and anchorage factors, and their regulation by phosphorylation, will be crucial to understanding the underlying mechanisms of synaptic plasticity.
Acknowledgements
We thank Ingo Greger and Charu Misra for critical reading of the manuscript, and Theresa Serra for help in its preparation. MF Barry is an Associate and EB Ziff an Investigator of the Howard Hughes Medical Institute.
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
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