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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Wisden, W. & Seeburg, P. H. Mammalian ionotropic glutamate receptors. Curr. Opin. Neurobiol. 3, 291–298 (1993).
Mammen, A. L., Huganir, R. L. & O'Brien, R. J. Redistribution and stabilization of cell surface glutamate receptors during synapse formation. J. Neurosci. 17, 7351–7358 (1997).
Archibald, K., Perry, M. J., Molnar, E. & Henley, J. M. Surface expression and metabolic half-life of AMPA receptors in cultured rat cerebellar granule cells. Neuropharmacology 37, 1345–1353 (1998).
Henley, J. M., Barker, E. A. & Glebov, O. O. Routes, destinations and delays: recent advances in AMPA receptor trafficking. Trends Neurosci. 34, 258–268 (2011).
Huganir, R. L. & Nicoll, R. A. AMPARs and synaptic plasticity: the last 25 years. Neuron 80, 704–717 (2013).
Nicoll, R. A. & Roche, K. W. Long-term potentiation: peeling the onion. Neuropharmacology 74, 18–22 (2013).
Sans, N. et al. Aberrant formation of glutamate receptor complexes in hippocampal neurons of mice lacking the GluR2 AMPA receptor subunit. J. Neurosci. 23, 9367–9373 (2003).
Lu, W. et al. Subunit composition of synaptic AMPA receptors revealed by a single-cell genetic approach. Neuron 62, 254–268 (2009).
Wenthold, R. J., Petralia, R. S., Blahos, J. II & Niedzielski, A. S. Evidence for multiple AMPA receptor complexes in hippocampal CA1/CA2 neurons. J. Neurosci. 16, 1982–1989 (1996).
Shi, S., Hayashi, Y., Esteban, J. A. & Malinow, R. Subunit-specific rules governing AMPA receptor trafficking to synapses in hippocampal pyramidal neurons. Cell 105, 331–343 (2001). This paper proposed the now widely accepted model that regulated addition of GluA1–GluA2-and continuous replacement of GluA2–GluA3-containing synaptic AMPARs provides the mechanism for how surface receptor number is established and maintained.
Kessels, H. W., Kopec, C. D., Klein, M. E. & Malinow, R. Roles of stargazin and phosphorylation in the control of AMPA receptor subcellular distribution. Nat. Neurosci. 12, 888–896 (2009).
Zhu, J. J., Esteban, J. A., Hayashi, Y. & Malinow, R. Postnatal synaptic potentiation: delivery of GluR4-containing AMPA receptors by spontaneous activity. Nat. Neurosci. 3, 1098–1106 (2000).
Bernard, V., Somogyi, P. & Bolam, J. P. Cellular, subcellular, and subsynaptic distribution of AMPA-type glutamate receptor subunits in the neostriatum of the rat. J. Neurosci. 17, 819–833 (1997).
Pelkey, K. A. et al. Pentraxins coordinate excitatory synapse maturation and circuit integration of parvalbumin interneurons. Neuron 85, 1257–1272 (2015).
Zamanillo, D. et al. Importance of AMPA receptors for hippocampal synaptic plasticity but not for spatial learning. Science 284, 1805–1811 (1999).
Hayashi, Y. et al. Driving AMPA receptors into synapses by LTP and CaMKII: requirement for GluR1 and PDZ domain interaction. Science 287, 2262–2267 (2000).
Lee, S. H., Simonetta, A. & Sheng, M. Subunit rules governing the sorting of internalized AMPA receptors in hippocampal neurons. Neuron 43, 221–236 (2004).
Granger, A. J., Shi, Y., Lu, W., Cerpas, M. & Nicoll, R. A. LTP requires a reserve pool of glutamate receptors independent of subunit type. Nature 493, 495–500 (2013). Contrary to the prevailing view, this paper reported the unexpected finding that there is no absolute requirement for any individual AMPAR subunit, or C-terminal protein interaction, for LTP.
Granger, A. J. & Nicoll, R. A. LTD expression is independent of glutamate receptor subtype. Front. Synapt. Neurosci. 6, 15 (2014).
Kim, C. H. et al. Persistent hippocampal CA1 LTP in mice lacking the C-terminal PDZ ligand of GluR1. Nat. Neurosci. 8, 985–987 (2005).
Kerr, J. M. & Blanpied, T. A. Subsynaptic AMPA receptor distribution is acutely regulated by actin-driven reorganization of the postsynaptic density. J. Neurosci. 32, 658–673 (2012).
Hosokawa, T., Mitsushima, D., Kaneko, R. & Hayashi, Y. Stoichiometry and phosphoisotypes of hippocampal AMPA-type glutamate receptor phosphorylation. Neuron 85, 60–67 (2015). Using biochemical approaches, this report suggests that there is almost no phosphorylation of GluA1 at S831 and S845, the two major sites identified by many previous papers as critical for AMPAR regulation.
Lee, H. K. et al. Phosphorylation of the AMPA receptor GluR1 subunit is required for synaptic plasticity and retention of spatial memory. Cell 112, 631–643 (2003). This study generated transgenic mice that express GluA1 with mutated phosphorylation sites and demonstrated that phosphorylation of GluA1 is required for LTD and LTP, and learning and memory.
Esteban, J. A. et al. PKA phosphorylation of AMPA receptor subunits controls synaptic trafficking underlying plasticity. Nat. Neurosci. 6, 136–143 (2003).
MacGillavry, H. D., Song, Y., Raghavachari, S. & Blanpied, T. A. Nanoscale scaffolding domains within the postsynaptic density concentrate synaptic AMPA receptors. Neuron 78, 615–622 (2013).
Nair, D. et al. Super-resolution imaging reveals that AMPA receptors inside synapses are dynamically organized in nanodomains regulated by PSD95. J. Neurosci. 33, 13204–13224 (2013).
Sheng, M. & Hoogenraad, C. C. The postsynaptic architecture of excitatory synapses: a more quantitative view. Annu. Rev. Biochem. 76, 823–847 (2007).
Steiner, P. et al. Destabilization of the postsynaptic density by PSD-95 serine 73 phosphorylation inhibits spine growth and synaptic plasticity. Neuron 60, 788–802 (2008).
Coombs, I. D. & Cull-Candy, S. G. Transmembrane AMPA receptor regulatory proteins and AMPA receptor function in the cerebellum. Neuroscience 162, 656–665 (2009).
Bats, C., Groc, L. & Choquet, D. The interaction between Stargazin and PSD-95 regulates AMPA receptor surface trafficking. Neuron 53, 719–734 (2007).
Chen, L. et al. Stargazing regulates synaptic targeting of AMPA receptors by two distinct mechanisms. Nature 408, 936–943 (2000). This paper reports that AMPAR subunit interaction with stargazin is required for surface expression of AMPARs and implies the widespread influence of TARPs in AMPAR trafficking.
Sumioka, A. Auxiliary subunits provide new insights into regulation of AMPA receptor trafficking. J. Biochem. 153, 331–337 (2013).
Opazo, P. et al. CaMKII triggers the diffusional trapping of surface AMPARs through phosphorylation of stargazin. Neuron 67, 239–252 (2010).
Opazo, P., Sainlos, M. & Choquet, D. Regulation of AMPA receptor surface diffusion by PSD-95 slots. Curr. Opin. Neurobiol. 22, 453–460 (2012).
Carta, M. et al. CaMKII-dependent phosphorylation of GluK5 mediates plasticity of kainate receptors. EMBO J. 32, 496–510 (2013).
Saglietti, L. et al. Extracellular interactions between GluR2 and N-cadherin in spine regulation. Neuron 54, 461–477 (2007).
Tai, C. Y., Kim, S. A. & Schuman, E. M. Cadherins and synaptic plasticity. Curr. Opin. Cell Biol. 20, 567–575 (2008).
Linhoff, M. W. et al. An unbiased expression screen for synaptogenic proteins identifies the LRRTM protein family as synaptic organizers. Neuron 61, 734–749 (2009).
Soler-Llavina, G. J. et al. Leucine-rich repeat transmembrane proteins are essential for maintenance of long-term potentiation. Neuron 79, 439–446 (2013). This study shows that LRRTM synaptic cell adhesion molecules are required for LTP because they maintain the surface expression of newly recruited synaptic AMPARs.
Makino, H. & Malinow, R. AMPA receptor incorporation into synapses during LTP: the role of lateral movement and exocytosis. Neuron 64, 381–390 (2009).
Kawahara, Y., Ito, K., Sun, H., Kanazawa, I. & Kwak, S. Low editing efficiency of GluR2 mRNA is associated with a low relative abundance of ADAR2 mRNA in white matter of normal human brain. Eur. J. Neurosci. 18, 23–33 (2003).
Wright, A. & Vissel, B. The essential role of AMPA receptor GluR2 subunit RNA editing in the normal and diseased brain. Front. Mol. Neurosci. 5, 34 (2012).
Isaac, J. T., Ashby, M. & McBain, C. J. The role of the GluR2 subunit in AMPA receptor function and synaptic plasticity. Neuron 54, 859–871 (2007).
Liu, S. J. & Zukin, R. S. Ca2+-permeable AMPA receptors in synaptic plasticity and neuronal death. Trends Neurosci. 30, 126–134 (2007).
Cull-Candy, S., Kelly, L. & Farrant, M. Regulation of Ca2+-permeable AMPA receptors: synaptic plasticity and beyond. Curr. Opin. Neurobiol. 16, 288–297 (2006).
Man, H. Y. GluA2-lacking, calcium-permeable AMPA receptors — inducers of plasticity? Curr. Opin. Neurobiol. 21, 291–298 (2011).
Washburn, M. S. & Dingledine, R. Block of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors by polyamines and polyamine toxins. J. Pharmacol. Exp. Ther. 278, 669–678 (1996).
Plant, K. et al. Transient incorporation of native GluR2-lacking AMPA receptors during hippocampal long-term potentiation. Nat. Neurosci. 9, 602–604 (2006).
Yang, Y., Wang, X. B. & Zhou, Q. Perisynaptic GluR2-lacking AMPA receptors control the reversibility of synaptic and spines modifications. Proc. Natl Acad. Sci. USA 107, 11999–12004 (2010).
Jaafari, N., Henley, J. M. & Hanley, J. G. PICK1 mediates transient synaptic expression of GluA2-lacking AMPA receptors during glycine-induced AMPA receptor trafficking. J. Neurosci. 32, 11618–11630 (2012).
He, K. et al. Stabilization of Ca2+-permeable AMPA receptors at perisynaptic sites by GluR1-S845 phosphorylation. Proc. Natl Acad. Sci. USA 106, 20033–20038 (2009).
Fortin, D. A. et al. Long-term potentiation-dependent spine enlargement requires synaptic Ca2+-permeable AMPA receptors recruited by CaM-kinase I. J. Neurosci. 30, 11565–11575 (2010).
Adesnik, H. & Nicoll, R. A. Conservation of glutamate receptor 2-containing AMPA receptors during long-term potentiation. J. Neurosci. 27, 4598–4602 (2007).
Gray, E. E., Fink, A. E., Sarinana, J., Vissel, B. & O'Dell, T. J. Long-term potentiation in the hippocampal CA1 region does not require insertion and activation of GluR2-lacking AMPA receptors. J. Neurophysiol. 98, 2488–2492 (2007).
Granger, A. J. & Nicoll, R. A. Expression mechanisms underlying long-term potentiation: a postsynaptic view, 10 years on. Phil. Trans. R. Soc. B 369, 20130136 (2014).
Ho, M. T. et al. Developmental expression of Ca2+-permeable AMPA receptors underlies depolarization-induced long-term depression at mossy fiber CA3 pyramid synapses. J. Neurosci. 27, 11651–11662 (2007).
Liu, S. Q. & Cull-Candy, S. G. Synaptic activity at calcium-permeable AMPA receptors induces a switch in receptor subtype. Nature 405, 454–458 (2000). This paper provided the first description of activity-induced changes in the AMPAR subunit composition from GluA2-lacking, Ca2+-permeable to GluA2-containing Ca2+-impermeable complexes at cerebellar stellate cell synapses.
Kelly, L., Farrant, M. & Cull-Candy, S. G. Synaptic mGluR activation drives plasticity of calcium-permeable AMPA receptors. Nat. Neurosci. 12, 593–601 (2009).
Turrigiano, G. G. The self-tuning neuron: synaptic scaling of excitatory synapses. Cell 135, 422–435 (2008).
Thiagarajan, T. C., Lindskog, M. & Tsien, R. W. Adaptation to synaptic inactivity in hippocampal neurons. Neuron 47, 725–737 (2005).
Aoto, J., Nam, C. I., Poon, M. M., Ting, P. & Chen, L. Synaptic signaling by all-trans retinoic acid in homeostatic synaptic plasticity. Neuron 60, 308–320 (2008).
Sutton, M. A. et al. Miniature neurotransmission stabilizes synaptic function via tonic suppression of local dendritic protein synthesis. Cell 125, 785–799 (2006).
Ogoshi, F. et al. Tumor necrosis-factor-alpha (TNF-α) induces rapid insertion of Ca2+-permeable α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA)/kainate (Ca-A/K) channels in a subset of hippocampal pyramidal neurons. Exp. Neurol. 193, 384–393 (2005).
Shepherd, J. D. et al. Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors. Neuron 52, 475–484 (2006).
Gainey, M. A., Hurvitz-Wolff, J. R., Lambo, M. E. & Turrigiano, G. G. Synaptic scaling requires the GluR2 subunit of the AMPA receptor. J. Neurosci. 29, 6479–6489 (2009).
Pellegrini-Giampietro, D. E., Bennett, M. V. & Zukin, R. S. Are Ca2+-permeable kainate/AMPA receptors more abundant in immature brain? Neurosci. Lett. 144, 65–69 (1992).
Pickard, L., Noel, J., Henley, J. M., Collingridge, G. L. & Molnar, E. Developmental changes in synaptic AMPA and NMDA receptor distribution and AMPA receptor subunit composition in living hippocampal neurons. J. Neurosci. 20, 7922–7931 (2000).
Monyer, H., Seeburg, P. H. & Wisden, W. Glutamate-operated channels — developmentally early and mature forms arise by alternative splicing. Neuron 6, 799–810 (1991).
Allen, N. J. Role of glia in developmental synapse formation. Curr. Opin. Neurobiol. 23, 1027–1033 (2013).
Suzuki, E., Kessler, M. & Arai, A. C. The fast kinetics of AMPA GluR3 receptors is selectively modulated by the TARPs γ4 and γ8. Mol. Cell. Neurosci. 38, 117–123 (2008).
Blair, M. G. et al. Developmental changes in structural and functional properties of hippocampal AMPARs parallels the emergence of deliberative spatial navigation in juvenile rats. J. Neurosci. 33, 12218–12228 (2013).
Mayer, M. L. Glutamate receptors at atomic resolution. Nature 440, 456–462 (2006).
Sukumaran, M., Penn, A. C. & Greger, I. H. AMPA receptor assembly: atomic determinants and built-in modulators. Adv. Exp. Med. Biol. 970, 241–264 (2012).
Nakagawa, T. The biochemistry, ultrastructure, and subunit assembly mechanism of AMPA receptors. Mol. Neurobiol. 42, 161–184 (2010).
Rossmann, M. et al. Subunit-selective N-terminal domain associations organize the formation of AMPA receptor heteromers. EMBO J. 30, 959–971 (2011).
Greger, I. H., Khatri, L. & Ziff, E. B. RNA editing at arg607 controls AMPA receptor exit from the endoplasmic reticulum. Neuron 34, 759–772 (2002).
Greger, I. H., Khatri, L., Kong, X. & Ziff, E. B. AMPA receptor tetramerization is mediated by Q/R editing. Neuron 40, 763–774 (2003).
Mah, S. J., Cornell, E., Mitchell, N. A. & Fleck, M. W. Glutamate receptor trafficking: endoplasmic reticulum quality control involves ligand binding and receptor function. J. Neurosci. 25, 2215–2225 (2005).
Greger, I. H., Ziff, E. B. & Penn, A. C. Molecular determinants of AMPA receptor subunit assembly. Trends Neurosci. 30, 407–416 (2007).
Brorson, J. R., Li, D. & Suzuki, T. Selective expression of heteromeric AMPA receptors driven by flip-flop differences. J. Neurosci. 24, 3461–3470 (2004).
Greger, I. H., Akamine, P., Khatri, L. & Ziff, E. B. Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis. Neuron 51, 85–97 (2006).
Kumar, S. S., Bacci, A., Kharazia, V. & Huguenard, J. R. A developmental switch of AMPA receptor subunits in neocortical pyramidal neurons. J. Neurosci. 22, 3005–3015 (2002).
Lu, W., Khatri, L. & Ziff, E. B. Trafficking of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA) receptor subunit GluA2 from the endoplasmic reticulum is stimulated by a complex containing Ca2+/calmodulin-activated kinase II (CaMKII) and PICK1 protein and by release of Ca2+ from internal stores. J. Biol. Chem. 289, 19218–19230 (2014).
Tomita, S. et al. Functional studies and distribution define a family of transmembrane AMPA receptor regulatory proteins. J. Cell Biol. 161, 805–816 (2003).
Vandenberghe, W., Nicoll, R. A. & Bredt, D. S. Interaction with the unfolded protein response reveals a role for stargazin in biosynthetic AMPA receptor transport. J. Neurosci. 25, 1095–1102 (2005).
Tomita, S., Nicoll, R. A. & Bredt, D. S. PDZ protein interactions regulating glutamate receptor function and plasticity. J. Cell Biol. 153, F19–F24 (2001).
Bokel, C., Dass, S., Wilsch-Brauninger, M. & Roth, S. Drosophila Cornichon acts as cargo receptor for ER export of the TGFα-like growth factor Gurken. Development 133, 459–470 (2006).
Sauvageau, E. et al. CNIH4 interacts with newly synthesized GPCR and controls their export from the endoplasmic reticulum. Traffic 15, 383–400 (2014).
Brockie, P. J. et al. Cornichons control ER export of AMPA receptors to regulate synaptic excitability. Neuron 80, 129–142 (2013).
Harmel, N. et al. AMPA receptors commandeer an ancient cargo exporter for use as an auxiliary subunit for signaling. PLoS ONE 7, e30681 (2012).
Hanley, J. G. Subunit-specific trafficking mechanisms regulating the synaptic expression of Ca2+-permeable AMPA receptors. Semin. Cell Dev. Biol. 27, 14–22 (2014).
Terashima, A. et al. An essential role for PICK1 in NMDA receptor-dependent bidirectional synaptic plasticity. Neuron 57, 872–882 (2008).
Lin, D. T. & Huganir, R. L. PICK1 and phosphorylation of the glutamate receptor 2 (GluR2) AMPA receptor subunit regulates GluR2 recycling after NMDA receptor-induced internalization. J. Neurosci. 27, 13903–13908 (2007).
Citri, A. et al. Calcium binding to PICK1 is essential for the intracellular retention of AMPA receptors underlying long-term depression. J. Neurosci. 30, 16437–16452 (2010).
Volk, L., Kim, C. H., Takamiya, K., Yu, Y. & Huganir, R. L. Developmental regulation of protein interacting with C kinase 1 (PICK1) function in hippocampal synaptic plasticity and learning. Proc. Natl Acad. Sci. USA 107, 21784–21789 (2010).
Petrini, E. M. et al. Endocytic trafficking and recycling maintain a pool of mobile surface AMPA receptors required for synaptic potentiation. Neuron 63, 92–105 (2009).
Schnell, E. et al. Direct interactions between PSD-95 and stargazin control synaptic AMPA receptor number. Proc. Natl Acad. Sci. USA 99, 13902–13907 (2002).
Tomita, S. et al. Stargazin modulates AMPA receptor gating and trafficking by distinct domains. Nature 435, 1052–1058 (2005).
Boehm, J., Ehrlich, I., Hsieh, H. & Malinow, R. Two mutations preventing PDZ-protein interactions of GluR1 have opposite effects on synaptic plasticity. Learn. Mem. 13, 562–565 (2006).
Mauceri, D., Cattabeni, F., Di Luca, M. & Gardoni, F. Calcium/calmodulin-dependent protein kinase II phosphorylation drives synapse-associated protein 97 into spines. J. Biol. Chem. 279, 23813–23821 (2004).
Wu, H., Nash, J. E., Zamorano, P. & Garner, C. C. Interaction of SAP97 with minus-end-directed actin motor myosin VI. Implications for AMPA receptor trafficking. J. Biol. Chem. 277, 30928–30934 (2002).
Loo, L. S., Tang, N., Al-Haddawi, M., Dawe, G. S. & Hong, W. A role for sorting nexin 27 in AMPA receptor trafficking. Nat. Commun. 5, 3176 (2014).
Hussain, N. K., Diering, G. H., Sole, J., Anggono, V. & Huganir, R. L. Sorting Nexin 27 regulates basal and activity-dependent trafficking of AMPARs. Proc. Natl Acad. Sci. USA 111, 11840–11845 (2014).
Liu, S. J. & Cull-Candy, S. G. Subunit interaction with PICK and GRIP controls Ca2+ permeability of AMPARs at cerebellar synapses. Nat. Neurosci. 8, 768–775 (2005).
Gardner, S. M. et al. Calcium-permeable AMPA receptor plasticity is mediated by subunit-specific interactions with PICK1 and NSF. Neuron 45, 903–915 (2005).
Dong, H. et al. GRIP: a synaptic PDZ domain-containing protein that interacts with AMPA receptors. Nature 386, 279–284 (1997).
Nishimune, A. et al. NSF binding to GluR2 regulates synaptic transmission. Neuron 21, 87–97 (1998).
Jackson, A. C. & Nicoll, R. A. The expanding social network of ionotropic glutamate receptors: TARPs and other transmembrane auxiliary subunits. Neuron 70, 178–199 (2011).
Haering, S. C., Tapken, D., Pahl, S. & Hollmann, M. Auxiliary subunits: shepherding AMPA receptors to the plasma membrane. Membranes (Basel) 4, 469–490 (2014).
Zheng, Y. et al. SOL-1 is an auxiliary subunit that modulates the gating of GLR-1 glutamate receptors in Caenorhabditis elegans. Proc. Natl Acad. Sci. USA 103, 1100–1105 (2006).
Schwenk, J. et al. Functional proteomics identify cornichon proteins as auxiliary subunits of AMPA receptors. Science 323, 1313–1319 (2009).
Kalashnikova, E. et al. SynDIG1: an activity-regulated, AMPA- receptor-interacting transmembrane protein that regulates excitatory synapse development. Neuron 65, 80–93 (2010).
Kirk, L. M. et al. Distribution of the SynDIG4/Proline rich transmembrane protein 1 in rat brain. J. Comp. Neurol. http://dx.doi.org/10.1002/cne.23945 (2015).
von Engelhardt, J. et al. CKAMP44: a brain-specific protein attenuating short-term synaptic plasticity in the dentate gyrus. Science 327, 1518–1522 (2010).
Farrow, P. et al. Auxiliary subunits of the CKAMP family differentially modulate AMPA receptor properties. eLife 4, e09693 (2015).
Shanks, N. F. et al. Differences in AMPA and kainate receptor interactomes facilitate identification of AMPA receptor auxiliary subunit GSG1L. Cell Rep. 1, 590–598 (2012).
Constals, A. et al. Glutamate-induced AMPA receptor desensitization increases their mobility and modulates short-term plasticity through unbinding from Stargazin. Neuron 85, 787–803 (2015).
Morimoto-Tomita, M. et al. Autoinactivation of neuronal AMPA receptors via glutamate-regulated TARP interaction. Neuron 61, 101–112 (2009).
Nakagawa, T., Cheng, Y., Ramm, E., Sheng, M. & Walz, T. Structure and different conformational states of native AMPA receptor complexes. Nature 433, 545–549 (2005).
Semenov, A., Moykkynen, T., Coleman, S. K., Korpi, E. R. & Keinanen, K. Autoinactivation of the stargazin-AMPA receptor complex: subunit-dependency and independence from physical dissociation. PLoS ONE 7, e49282 (2012).
Soto, D., Coombs, I. D., Kelly, L., Farrant, M. & Cull-Candy, S. G. Stargazin attenuates intracellular polyamine block of calcium-permeable AMPA receptors. Nat. Neurosci. 10, 1260–1267 (2007).
Soto, D. et al. Selective regulation of long-form calcium-permeable AMPA receptors by an atypical TARP, γ-5. Nat. Neurosci. 12, 277–285 (2009).
Bats, C., Soto, D., Studniarczyk, D., Farrant, M. & Cull-Candy, S. G. Channel properties reveal differential expression of TARPed and TARPless AMPARs in stargazer neurons. Nat. Neurosci. 15, 853–861 (2012).
Jackson, A. C. et al. Probing TARP modulation of AMPA receptor conductance with polyamine toxins. J. Neurosci. 31, 7511–7520 (2011).
Studniarczyk, D., Coombs, I., Cull-Candy, S. G. & Farrant, M. TARP γ-7 selectively enhances synaptic expression of calcium-permeable AMPARs. Nat. Neurosci. 16, 1266–1274 (2013).
Herring, B. E. et al. Cornichon proteins determine the subunit composition of synaptic AMPA receptors. Neuron 77, 1083–1096 (2013).
Chater, T. E. & Goda, Y. The role of AMPA receptors in postsynaptic mechanisms of synaptic plasticity. Front. Cell. Neurosci. 8, 401 (2014).
Wang, J. Q. et al. Roles of subunit phosphorylation in regulating glutamate receptor function. Eur. J. Pharmacol. 728, 183–187 (2014).
Lee, H. K., Barbarosie, M., Kameyama, K., Bear, M. F. & Huganir, R. L. Regulation of distinct AMPA receptor phosphorylation sites during bidirectional synaptic plasticity. Nature 405, 955–959 (2000).
Lu, W. & Roche, K. W. Posttranslational regulation of AMPA receptor trafficking and function. Curr. Opin. Neurobiol. 22, 470–479 (2012).
Roche, K. W., O'Brien, R. J., Mammen, A. L., Bernhardt, J. & Huganir, R. L. Characterization of multiple phosphorylation sites on the AMPA receptor GluR1 subunit. Neuron 16, 1179–1188 (1996).
Kristensen, A. S. et al. Mechanism of Ca2+/calmodulin-dependent kinase II regulation of AMPA receptor gating. Nat. Neurosci. 14, 727–735 (2011).
Banke, T. G. et al. Control of GluR1 AMPA receptor function by cAMP-dependent protein kinase. J. Neurosci. 20, 89–102 (2000).
Lee, H. K., Takamiya, K., He, K., Song, L. & Huganir, R. L. Specific roles of AMPA receptor subunit GluR1 (GluA1) phosphorylation sites in regulating synaptic plasticity in the CA1 region of hippocampus. J. Neurophysiol. 103, 479–489 (2010).
Steinberg, J. P. et al. Targeted in vivo mutations of the AMPA receptor subunit GluR2 and its interacting protein PICK1 eliminate cerebellar long-term depression. Neuron 49, 845–860 (2006).
Luchkina, N. V. et al. Developmental switch in the kinase dependency of long-term potentiation depends on expression of GluA4 subunit-containing AMPA receptors. Proc. Natl Acad. Sci. USA 111, 4321–4326 (2014).
Henley, J. M., Craig, T. J. & Wilkinson, K. A. Neuronal SUMOylation: mechanisms, physiology, and roles in neuronal dysfunction. Physiol. Rev. 94, 1249–1285 (2014).
Sanderson, J. L. et al. AKAP150-anchored calcineurin regulates synaptic plasticity by limiting synaptic incorporation of Ca2+-permeable AMPA receptors. J. Neurosci. 32, 15036–15052 (2012).
Kim, S. & Ziff, E. B. Calcineurin mediates synaptic scaling via synaptic trafficking of Ca2+-permeable AMPA receptors. PLoS Biol. 12, e1001900 (2014).
Diering, G. H., Gustina, A. S. & Huganir, R. L. PKA–GluA1 coupling via AKAP5 controls AMPA receptor phosphorylation and cell-surface targeting during bidirectional homeostatic plasticity. Neuron 84, 790–805 (2014).
Guire, E. S., Oh, M. C., Soderling, T. R. & Derkach, V. A. Recruitment of calcium-permeable AMPA receptors during synaptic potentiation is regulated by CaM-kinase I. J. Neurosci. 28, 6000–6009 (2008).
Hampel, H. et al. The future of Alzheimer's disease: the next 10 years. Prog. Neurobiol. 95, 718–728 (2011).
Shankar, G. M. et al. Amyloid-β protein dimers isolated directly from Alzheimer's brains impair synaptic plasticity and memory. Nat. Med. 14, 837–842 (2008).
Walsh, D. M. & Selkoe, D. J. Aβ oligomers — a decade of discovery. J. Neurochem. 101, 1172–1184 (2007).
Zhao, W. Q. et al. Inhibition of calcineurin-mediated endocytosis and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors prevents amyloid β oligomer-induced synaptic disruption. J. Biol. Chem. 285, 7619–7632 (2010).
Whitcomb, D. J. et al. Intracellular oligomeric amyloid-beta rapidly regulates GluA1 subunit of AMPA receptor in the hippocampus. Sci. Rep. 5, 10934 (2015).
Spaethling, J. M., Klein, D. M., Singh, P. & Meaney, D. F. Calcium-permeable AMPA receptors appear in cortical neurons after traumatic mechanical injury and contribute to neuronal fate. J. Neurotrauma 25, 1207–1216 (2008).
Grooms, S. Y., Opitz, T., Bennett, M. V. & Zukin, R. S. Status epilepticus decreases glutamate receptor 2 mRNA and protein expression in hippocampal pyramidal cells before neuronal death. Proc. Natl Acad. Sci. USA 97, 3631–3636 (2000).
Yamashita, T. & Kwak, S. The molecular link between inefficient GluA2 Q/R site-RNA editing and TDP-43 pathology in motor neurons of sporadic amyotrophic lateral sclerosis patients. Brain Res. 1584, 28–38 (2014).
Sommer, B., Kohler, M., Sprengel, R. & Seeburg, P. H. RNA editing in brain controls a determinant of ion flow in glutamate-gated channels. Cell 67, 11–19 (1991).
Verdoorn, T. A., Burnashev, N., Monyer, H., Seeburg, P. H. & Sakmann, B. Structural determinants of ion flow through recombinant glutamate receptor channels. Science 252, 1715–1718 (1991).
Hestrin, S. Different glutamate receptor channels mediate fast excitatory synaptic currents in inhibitory and excitatory cortical neurons. Neuron 11, 1083–1091 (1993).
Clem, R. L. & Barth, A. Pathway-specific trafficking of native AMPARs by in vivo experience. Neuron 49, 663–670 (2006).
Goel, A. et al. Cross-modal regulation of synaptic AMPA receptors in primary sensory cortices by visual experience. Nat. Neurosci. 9, 1001–1003 (2006).
Goel, A. et al. Phosphorylation of AMPA receptors is required for sensory deprivation-induced homeostatic synaptic plasticity. PLoS ONE 6, e18264 (2011).
Clem, R. L., Anggono, V. & Huganir, R. L. PICK1 regulates incorporation of calcium-permeable AMPA receptors during cortical synaptic strengthening. J. Neurosci. 30, 6360–6366 (2010).
Bellone, C. & Luscher, C. mGluRs induce a long-term depression in the ventral tegmental area that involves a switch of the subunit composition of AMPA receptors. Eur. J. Neurosci. 21, 1280–1288 (2005).
Bellone, C. & Luscher, C. Cocaine triggered AMPA receptor redistribution is reversed in vivo by mGluR-dependent long-term depression. Nat. Neurosci. 9, 636–641 (2006).
Conrad, K. L. et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118–121 (2008).
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.
Author information
Authors and Affiliations
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
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.
Rights and permissions
About this article
Cite this article
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
Published:
Issue Date:
DOI: https://doi.org/10.1038/nrn.2016.37
This article is cited by
-
Synaptopodin is required for long-term depression at Schaffer collateral-CA1 synapses
Molecular Brain (2024)
-
Quantifying AMPARs with 99mTc-omberacetam: a novel diagnostic radiotracer for ischemic stroke
Journal of Umm Al-Qura University for Applied Sciences (2024)
-
Effects of DeSUMOylated Spastin on AMPA Receptor Surface Delivery and Synaptic Function Are Enhanced by Phosphorylating at Ser210
Molecular Neurobiology (2024)
-
Liraglutide Reduces Alcohol Consumption, Anxiety, Memory Impairment, and Synapse Loss in Alcohol Dependent Mice
Neurochemical Research (2024)
-
p85S6K sustains synaptic GluA1 to ameliorate cognitive deficits in Alzheimer’s disease
Translational Neurodegeneration (2023)