Neuron Review

The AMPA Receptor Code of Synaptic Plasticity

Graham H. Diering1 and Richard L. Huganir2,3,* 1Department of Cell Biology and Physiology, and Neuroscience Center, University of North Carolina, Chapel Hill, NC 27514, USA 2Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA 3Kavli Neuroscience Discovery Institute, Johns Hopkins University, Baltimore, MD 21205, USA *Correspondence: [email protected] https://doi.org/10.1016/j.neuron.2018.10.018

Changes in the properties and postsynaptic abundance of AMPA-type glutamate receptors (AMPARs) are major mechanisms underlying various forms of synaptic plasticity, including long-term potentiation (LTP), long-term depression (LTD), and homeostatic scaling. The function and the trafficking of AMPARs to and from synapses is modulated by specific AMPAR GluA1–GluA4 subunits, subunit-specific protein interactors, auxiliary subunits, and posttranslational modifications. Layers of regulation are added to AMPAR tetramers through these different interactions and modifications, increasing the computational power of synapses. Here we review the reliance of synaptic plasticity on AMPAR variants and propose ‘‘the AMPAR code’’ as a conceptual framework. The AMPAR code suggests that AMPAR variants will be predictive of the types and extent of synaptic plasticity that can occur and that a hierarchy exists such that certain AMPARs will be disproportionally recruited to synapses during LTP/homeostatic scaling up, or removed during LTD/ homeostatic scaling down.

Introduction Ongoing information processing in the brain requires fast Synapses in the CNS undergo bidirectional changes in synaptic excitatory transmission, which relies on the immediate comple- strength, a process referred to as synaptic plasticity. These ment of postsynaptic AMPARs, whose channel properties are changes occur locally at individual synapses, during long-term subject to regulation. The types, thresholds, and range of potentiation (LTP) or long-term depression (LTD), collectively synaptic plasticity available for any synapse is likewise deter- referred to as Hebbian plasticity, or globally during homeostatic mined by the nature of the AMPARs already at synapses that scaling (Huganir and Nicoll, 2013; Turrigiano, 2008). It is widely could be modified or those that can be added to synapses dur- believed that changes in synaptic strength through Hebbian ing potentiation or removed during depression. Therefore, both plasticity form the cellular basis of learning and memory, while ongoing information processing and potential plasticity are homeostatic scaling is an important mechanism for bidirectional subject to the types or modifications of AMPARs. Here we pro- regulation of neuronal excitability for maintaining synaptic pose the model of an AMPAR code of synaptic plasticity. This strength within a dynamic range. A primary mechanism in the code suggests that AMPAR subunit combinations, assembly in control of synaptic strength during plasticity is an alteration in larger protein complexes, and PTMs may be a mode of infor- the number, composition, and biophysical properties of AMPA- mation storage involved in synaptic computation, plasticity, type glutamate receptors (AMPARs) in the postsynaptic mem- and learning and memory. In 2001, Jenuwein and Allis pro- brane (Huganir and Nicoll, 2013; Malinow and Malenka, 2002). posed the histone code, where the myriad PTMs of histone AMPARs are glutamate-gated ion channels that mediate the proteins, including phosphorylation, methylation, and acetyla- majority of fast excitatory synaptic transmission in the brain. tion, form combinatorial effects that considerably enhance the Four subunits, GluA1–GluA4 , assemble into tetramers to make informational capacity of the genetic code. Certain combina- up the core functional ion channel, with different combinations tions of histone modifications would be highly predictive of conferring unique cellular trafficking behaviors and biophysical regional chromatin structure and gene expression (Jenuwein characteristics (Shepherd and Huganir, 2007). Further, the traf- and Allis, 2001; Taverna et al., 2007). Unlike histones, which ficking, synapse anchoring, and single-channel properties of remain tightly associated with chromatin, AMPARs are highly AMPARs are regulated by subunit-specific protein binding dynamic, undergoing continuous endocytosis, exocytosis, partners and auxiliary subunits, and a large number of posttrans- lateral diffusion in the plane of the membrane, reversible trap- lational modifications (PTMs), including phosphorylation, ubiqui- ping at synapses at the postsynaptic density (PSD), and tination, glycosylation, palmitoylation, and S-nitrosylation (Hu- modifications in channel properties (Opazo et al., 2012; Huganir ganir and Nicoll, 2013; Lu and Roche, 2012; Widagdo et al., and Nicoll, 2013; Malinow and Malenka, 2002). Thus, the num- 2017; Lussier et al., 2015). Moreover, many modifications and in- ber and function of AMPARs contained within synapses is teractions have been shown to occur in combinations or to have dictated by a series of equilibriums and by individual channel feedback effects on neighboring modification sites or protein in- properties. The dynamic nature of AMPARs suggests that the teractions, such that certain combinations of PTMs and interac- AMPAR code will function by shifting equilibriums in favor of tions may be favored or inhibited. synaptic accumulation or removal, and by altering ion channel

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A Figure 1. AMPAR Posttranslational amino terminal domain: ~56% identical Modifications and the AMPAR Code (A) Schematic of AMPAR structure. % identity in- ligand binding domain: ~90% identical dicates the identity of each domain between the GluA1 and GluA4 subunits. transmembrane region and ion pore: ~90% identical (B) Amino acid sequences of GluA1–GluA4 C-ter- minal tails with known posttranslational modifi- cytoplasmic carboxy terminal tails: 24-78% identical cations indicated. Modifications with a ‘‘?’’ are known to occur but the modified amino acid has B not been identified. (C) Schematic of known interactions between GluA1 AMPAR posttranslational modifications.

811 818 831 840 845 863 868 875

GluA2 phosphorylation ? palmitoylation 836 863 870 876 880 882 ubiquitination Subunit Combinations GluA3 Nitrosylation AMPAR subunits contain highly conserved ? ligand binding and transmembrane do- 841 881 885 O-glycnacylation mains that allow glutamate binding and GluA4 channel pore assembly, respectively, ? but are divergent in their extracellular 817 842 amino-terminal domains and cytoplasmic carboxy-terminal tails, which are subject to PTMs ( Shepherd and Huganir, 2007) C GluA1 C811 palmitoylation GluA1 C875 nitrosylation GluA1 S845 phosphorylation (Figure 1). Traditionally, AMPARs have impairs S818 phosphorylation enhances S831 phosphorylation impairs K868 ubiquitination been divided into long- and short-tail groups: GluA1, GluA4, and a splice- variant of GluA2 (GluA2L) in the long-tail C811 limits S831 S845 group, and GluA2, GluA3, and a splice- S818 exocytosis C875 K868 variant of GluA4 (GluA4S) in the short- promotes 4.1N binding exocytosis tail group (Shepherd and Huganir, 2007). and LTP Earlier studies suggest that long-tailed GluA1 S831 and S845 phosphorylation GluA2/3 Y876 dephosphorylation Unkown interaction between AMPARs are recruited to synapses in an act synergistically for maximal LTP allows for S880 phosphorylation GluA2/3 phosphorylation and ubiquitination activity-depende nt manner, while short- tailed AMPARs undergo constitutive pS831 promotes ? cycling in and out of synapses (Shi et al., targeting to the PSD K870 K882 2001; Hayashi et al., 2000). GluA1– S831 Y876 Y876 GluA3 are expressed in the majority of S845 BRAG2 S880 S880 pS845 promotes GEF activity neurons in the nervous system while targeting/retention reduce GRIP1/2 binding GluA4 is primarily expressed early in life on the cell surface (Zhu et al., 2000), and in the mature brain GluA4 is primarily expressed in cerebellar granule neurons, in certain properties. Each step of synapse targeting is subject to AMPAR interneuron populations, certain circuits responsible for audito ry subunit composition, auxiliary subunit interaction, and PTMs. If processing, and is absent from the majority of excitatory pyrami- an AMPAR code exists, specific AMPAR compositions and dal neurons (Schwenk et al., 2014; von Gersdorff and Borst, PTMs should occur in a predictable manner and result in spe- 2002; Pelkey et al., 2015). cific changes in AMPAR dynamics or synapse function. For In hippocampal CA1 neurons the majority of AMPARs is made each type of plasticity, certain AMPAR variants will be preferen- up from GluA1/GluA2 and GluA2/GluA3 subunit combinations, tially added or removed from synapses or undergo selective with a small contribution of GluA1 homomers (Wenthold et al., changes in channel properties. In this review, we will summa- 1996). In this classic study, Wenthold et al. also detected a small rize what is known of how different AMPAR subunits, auxiliary amount of GluA1/GluA3 heteromers (Wenthold et al., 1996), subunits, PTMs, and protein binding partners impact synapse which have since been overlooked, but never discredited. Based function and explore the emerging themes of the AMPAR on this study, it has been assumed that the subunit combinations code. While the histone code may not yet have been ‘‘trans- in the rest of the brain are largely similar; however, AMPAR sub- lated,’’ the concept has proven to be highly influential in the unit combinations have not been systematically analyzed field of epigenetics (Taverna et al., 2007). We propose that a throughout the brain, though the relative expression levels of similar concept will serve as a valuable framework to assemble the AMPAR subunits do show regional variations (Schwenk a large volume of literature on the role of AMPARs in synaptic et al., 2014), suggesting that AMPAR composition will vary with plasticity. brain region (Lu et al., 2009). As mentioned above, it has been

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suggested that long-tailed AMPARs are primarily targeted to AMPAR tetramers may assemble with 1–4 TARP or CNIH sub- synapses in response to neuronal activity, such as during the in- units, although the stoichiometry of native receptors may vary. duction of LTP, while short-tailed receptors are constitutively CNIH2/CNIH3 seems to compete with TARPs for the same bind- targeted to synapses (Shi et al., 2001; Hayashi et al., 2000). ing sites, showing that CNIH proteins regulate TARP-AMPAR in- Some of these earlier studies relied on overexpression of teractions (Straub and Tomita, 2012; Herring et al., 2013). GluA1 or GluA2 in young organotypic hippocampal slices, which TARPs contain four transmembrane domains and a highly results in the biased synthesis of homomeric receptors. Since basic cytosolic C-terminal tail that also contains a PDZ-ligand the majority of AMPARs in the brain are heteromers, broad that has been shown to interact with PSD95 and other MAGUK conclusions regarding long- and short-tailed receptors may be scaffolds (Nicoll et al., 2006). TARPs have been shown to stabi- oversimplified. lize AMPARs both on the cell surface and at synapses (Bats A major distinction in AMPARs is between GluA2-containing et al., 2007; Sheng et al., 2018), and loss of TARPs results in and GluA2-lacking receptors. The vast majority of GluA2 decreased AMPAR expression, suggesting that ‘‘TARPless’’ mRNA is subjected to RNA editing converting a conserved gluta- AMPARs become unstable (Fukaya et al., 2006; Chen et al., mine 607 in the channel pore to arginine. The result of this 2000). TARPs significantly slow AMPAR deactivation and desen- modification is that GluA2 containing receptors have a linear cur- sitization kinetics (Menuz et al., 2008; Cho et al., 2007), likely rent-voltage (I-V) relationship and are impermeable to Ca2+, through interaction of extracellular loops of the TARP molecules while GluA2-lacking receptors show high conductance and rapid and the ligand binding domains of AMPARs (Cais et al., 2014). decay kinetics, inward rectification due to voltage-dependent The positively charged C terminus of TARPs interacts strongly block by intracellular polyamines, and are permeable to Ca2+; with membrane lipids, promoting the stabilization of AMPARs thus, GluA2-lacking receptors are usually referred to as cal- on the cell surface, but this TARP-lipid interaction prevents cium-permeable AMPARs (CP-AMPARs) (Burnashev et al., TARP binding to PSD95. The C terminus contains multiple phos- 1992). CP-AMPARs, the majority of which are likely to be phorylation sites for CaMKII, PKC, and PKA. Phosphorylation GluA1 homomers, are broadly detected in synapses in early reduces the interaction with membrane lipids and facilitates development. After postnatal day 14 in rodents, CP-AMPARs interaction with PSD95, serving to trap the TARP/AMPAR com- are rapidly lost from synapses in the majority of neurons and plex with the PSD (Opazo et al., 2012; Bats et al., 2007; Sheng are almost undetectable in the majority of synapses onto excit- et al., 2018). A recent study that used knockin mutations demon- atory pyramidal neurons in the mature brain. CP-AMPARs strated that two key CaMKII phosphorylation sites on TARP g-8, continue to be expressed at synapses in certain GABAergic neu- S277 and S281, are important mediators of hippocampal LTP rons including parvalbumin and somatostatin-positive neurons and learning and memory (Park et al., 2016). and in auditory centers throughout life (Studniarczyk et al., CNIH2/CNIH3 proteins promote the surface targeting of 2013; Sanchez et al., 2010; von Gersdorff and Borst, 2002; Pel- AMPARs and also slow the decay kinetics, similar to TARPs key et al., 2015). Many studies have reported the appearance of (Straub and Tomita, 2012; Boudkkazi et al., 2014). CNIH and CP-AMPARs at specific synapses during the induction of certain TARPs likely compete for the same AMPAR binding sites (Straub forms of synaptic plasticity including LTP, LTD, and homeostatic and Tomita, 2012; Herring et al., 2013), and so one possible func- scaling up, or following certain behavioral manipulations such as tion of CNIH is to regulate the stoichiometry of TARP interaction, fear conditioning or repeated cocaine administration and with- tuning the channel properties of the associated AMPARs. Her- drawal (Clem and Huganir, 2010; Plant et al., 2006; Kim and ring et al. (2013) have shown that loss of CNIH2/CNIH3 from hip- Ziff, 2014; Soares et al., 2013; Sanderson et al., 2016; McCutch- pocampus led to a selective decrease in the synaptic activity of eon et al., 2011). These receptors have faster decay kinetics but GluA1-containing receptors. TARP g-8 effectively prevented large conductance, enhancing synaptic transmission, and may CNIH2/CNIH3 interaction with GluA2/GluA3 heteromeric recep- activate unique Ca2+-sensitive signaling pathways that lead to tors, suggesting that CNIH proteins may control the subunit an opening of a metaplastic state, in which synapses become composition of synaptic AMPARs (Herring et al., 2013). CNIH primed for LTD or LTP (Clem and Huganir, 2010; Sanderson PTMs have not been well characterized but are likely to add et al., 2016). complexity to their role in AMPAR regulation. The ability of the AMPAR core to interact with auxiliary sub- Auxiliary Subunits units in a mixed stoichiometry, the selective interaction of auxil- In addition to the core pore-forming AMPAR tetramer, AMPARs iary subunits with certain AMPAR subunit combinations, and the associate with several other proteins that have come to be role of auxiliary proteins in the effect of AMPAR PTMs substan- recognized as auxiliary subunits. The best studied of these are tially increase the functional complexity of the AMPAR code. the Transmembrane AMPAR Regulatory Proteins (TARPs), g-2 The remainder of this review will focus on the core subunits of (stargazin), g-3, g-4, g-5, g-7, and g-8 (Tomita et al., 2003), the AMPAR and synaptic plasticity. The important role of AMPAR and the cornichon-like proteins CNIH2/CNIH3 (Schwenk et al., auxiliary subunits in synapse function and plasticity is an ongoing 2009). TARPs and CNIH2/CNIH3 regulate AMPAR channel prop- topic of active research (Brechet et al., 2017; Sheng et al., 2018). erties and cellular and synaptic trafficking (Straub and Tomita, 2012; Maher et al., 2017; Jacobi and von Engelhardt, 2017). Posttranslational Modifications of AMPAR Subunits Biochemical and proteomic studies have isolated native AMPARs are subject to modification of the cytosolic C terminus by AMPARs in complex with TARPs and CNIH and further demon- phosphorylation, palmitoylation, ubiquitination, S-nitrosylation, strate the presence of tripartite AMPAR/TARP/CNIH complexes. and potentially O-GlyNAcylation (Figure 1B). Phosphorylation is

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the most extensively characterized type of modification and many AMPAR (Huganir and Nicoll, 2013; Herring and Nicoll, 2016; sites have been identified. AMPARs are substrates for cAMP- Poncer et al., 2002; Benke et al., 1998). The increase in AMPAR dependent kinase (PKA) and cGMP-dependent kinase (PKG) content within the PSD is supplied by immediately available non- (GluA1 S845; GluA4 S842), protein kinase C (PKC) (GluA1 S818/ synaptic pools of diffusing AMPARs within the plane of the S831/T840; GluA2 S863/S880), Ca2+/calmodulin-dependent ki- plasma membrane, which in turn are replenished by exocytosis nase II (CaMKII) (GluA1 S567/S831), Casein kinase II (GluA1 of intracellular pools of AMPARs localized in recycling endo- S579; GluA2 S588), PAK3 (GluA1 S863), and Src family tyrosine ki- somes. The exocytosis, lateral diffusion, PSD trapping, and nase (GluA2 Y876) (Roche et al., 1996; Barria et al., 1997a, 1997b; changes in single-channel properties are all subject to regulation Esteban et al., 2003; Boehm et al., 2006; Chung et al., 2000; Lee by PTMs and protein interactions (Huganir and Nicoll, 2013; Ang- et al., 2007; Lu et al., 2010; Lussier et al., 2014, 2015; Hussain gono and Huganir, 2012; Lu and Roche, 2012). et al., 2015; Hayashi and Huganir, 2004). The GluA2 Y876 and GluA1 directly interacts with the cytoskeletal scaffold protein S880 phosphorylation sites are conserved in GluA3 (GluA3 Y881 4.1N through the C-terminal juxtamembrane region, and this and S885) and are most likely also phosphorylated (Figure 1B). interaction promotes activity-dependent exocytosis of GluA1 In particular, the best-understood phosphorylations occur on from intracellular endosomes (Lin et al., 2009; Anggono and Hu- GluA1, S831 and S845, and GluA2 S880. AMPAR phosphorylation ganir, 2012). Palmitoylation of GluA1 C811 prevents interaction can impact single-channel properties and cellular trafficking dur- with 4.1N and reduces PKC-mediated phosphorylation of nearby ing synaptic plasticity as described in greater detail below. S818 (Figure 1C) (Lin et al., 2009). Conversely, phosphorylation All four AMPAR subunits are palmitoylated at a conserved of GluA1 S818 increases interaction with 4.1N and is necessary cysteine residue in the C-terminal juxtamembrane region for activity-dependent exocytosis (Lin et al., 2009). During hippo- (GluA1 C811, GluA2 C836, GluA3 C841, GluA4 C817) and a campal LTP, PKC is activated to increase GluA1 S818 phosphor- second site within the transmembrane domain TM2 (Hayashi ylation, and a peptide mimicking phospho-GluA1 S818 or et al., 2005). All four AMPAR subunit are also ubiquitinated. shRNA-mediated knockdown of 4.1N both lead to decay of hip- The major sites of ubiquitination on GluA1 and GluA2 have pocampal LTP back to baseline, suggesting that the PKC/4.1N- been mapped to GluA1 K868 and GluA2 K870/K882 (Widagdo mediated increase in GluA1 exocytosis is necessary to maintain et al., 2015, 2017; Lussier et al., 2015). GluA1 undergoes LTP (Lin et al., 2009; Boehm et al., 2006). NMDA receptor (NMDAR) and nNOS-dependent S-nitrosylation Phosphorylation of GluA1 S831 and S845 are both strongly on C875 (Selvakumar et al., 2013). GluA2, but not GluA1, may be associated with LTP (Huganir and Nicoll, 2013; Lee et al., modified by O-GlcNAcylation on an unidentified cytosolic serine 2003; Barria et al., 1997b; Lee et al., 2000). NMDAR-dependent (Taylor et al., 2014). LTP requires Ca2+ influx leading to activation of CaMKII/PKC, Many of the AMPAR PTMs have been shown to be regulated which directly phosphorylate GluA1 S831, increasing GluA1 sin- and required during synaptic plasticity, including LTP, LTD, ho- gle-channel conductance and promoting GluA1 targeting to the meostatic scaling, neuromodulator-mediated plasticity, as well PSD (Mammen et al., 1997; Barria et al., 1997a; Derkach et al., as during certain animal behaviors. Arguably the strongest evi- 1999; Kristensen et al., 2011; Barria et al., 1997b). PKA can be dence for the role of AMPAR PTMs comes from knockin mutant activated by Ca2+-sensitive adenyl-cyclase or downstream of mice in which specific amino acids have been mutated to pre- neuromodulators signaling through their Gs-coupled receptors, vent or mimic certain modifications. In order to understand the such as the b-adrenergic receptor or D1-type dopamine recep- AMPAR code we must understand the role of each AMPAR sub- tors, leading to phosphorylation of GluA1 S845 (Joiner et al., unit and modification as well as the various combinatorial ef- 2010; Sun et al., 2005). Phosphorylation of S845 increases sin- fects. As an example, GluA1 undergoes 11 known PTMs, each gle-channel open probability and also promotes GluA1 targeting of which can occur independently and reversibly (7 phosphoryla- or retention to the cell surface (Banke et al., 2000; Oh et al., 2006; tions, 2 palmitoylations, 1 S-nitrosylation, 1 ubiquitination), al- Man et al., 2007). Mice containing knock-,in mutations in S831 lowing for 211, or 2,048, possible modified variants of GluA1, and S845 (S831A/S845A) that eliminate phosphorylation of these each of which may be expected to have subtly different proper- sites lack LTD (see below) and have partially impaired hippocam- ties. This number is further multiplied when considering hetero- pal LTP (Lee et al., 2003). However, the phosphorylation of GluA1 meric AMPARs. It is likely that additional modifications remain S831 and S845 can occur completely independently, and while to be discovered. In some cases, it has been shown that certain single S845A knockin mutation still eliminated LTD, the single AMPAR PTMs can influence others (Figure 1C), either by inhibit- S831A or S845A knockin mutations do not impair LTP of the ing or promoting the neighboring modification, suggesting that of Schaffer collateral-CA1 synapses in the hippocampus, suggest- all possible AMPAR variants some will be favored. In the ing a synergistic role of these two phosphorylation sites on LTP following sections we will review the role of AMPAR PTMs in expression (Lee et al., 2010). Under basal conditions in cultured different forms of synaptic plasticity and explore the emerging neurons and in mouse forebrain, approximately 15%–20% of themes of the AMPAR code. GluA1 is phosphorylated at S831 or S845, but only a small frac- tion of GluA1 is dually phosphorylated (Diering et al., 2016). The The AMPAR Code and LTP phosphorylated fraction of total GluA1 can increase to close to GluA1 and LTP 50% upon strong stimulation of PKC/PKA. Similarly, exposure The major form of LTP identified in the brain, NMDAR-dependent of mice to an enriched environment also greatly increases the LTP, is the result of increased AMPAR density in the postsyn- population of GluA1, showing dual S831/S845 phosphorylation aptic membrane and/or single-channel conductance of the (Figure 1C) (Diering et al., 2016). Compared to total membrane

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fractions, phospho-S831 receptors are enriched in the PSD can activate USP8, a de-ubiquitinating enzyme that acts on under basal conditions, whereas phospho-S845 receptors are AMPARs (Scudder et al., 2014), potentially limiting AMPAR ubiq- not (Diering et al., 2016), suggesting that S831 phosphorylation uitination during LTP. plays a role in targeting to the PSD or stabilization within the The role of CP-AMPARs, likely GluA1 homomers, in LTP re- PSD. Phosphorylation of GluA1 S845 plays a role in promoting mains controversial. At most synapses onto glutamatergic neu- GluA1 targeting to the cell surface and/or stabilization of GluA1 rons, synaptic levels of CP-AMPARs are very low. However, it on the cell-surface by enhancing GluA1 recycling and limiting has been reported that CP-AMPARs are present at perisynaptic endocytosis (Ehlers, 2000; Oh et al., 2006; Man et al., 2007). sites and can be rapidly and transiently recruited to synapses Neuromodulators, such as noradrenaline, can lower the immediately following the induction of LTP (He et al., 2009; Plant threshold for LTP, and this effect is blocked by GluA1 phos- et al., 2006; Guire et al., 2008; Yang et al., 2010). Other studies pho-deficient S831A/S845A knockin mutations (Hu et al., have refuted this observation (Adesnik and Nicoll, 2007; Gray 2007), whereas GluA1 phospho-mimetic S831D/S845D knockin et al., 2007). The presence of perisynaptic CP-AMPARs as well mutations show a lowered threshold for LTP that occludes the as their recruitment to synapses requires signaling from PKA effect of noradrenaline (Makino et al., 2011). These findings, and the S845 phosphorylation site (He et al., 2009; Clem and Hu- together with several previous studies, support a model where ganir, 2010; Sanderson et al., 2016). While the induction proto- PKA-mediated phosphorylation of GluA1 S845 promotes the cols vary somewhat between these studies, recent data offer surface trafficking of the receptor, lowering the threshold needed some explanation for the discrepancy. Sanderson et al., show to induce LTP. However, additional signaling from CaMKII is that in acute hippocampal slices from mice 11–14 days old, needed to promote GluA1 targeting to the PSD for maximal LTP of SC-CA1 synapses can be blocked by IEM1460, an inhib- LTP (Figure 1) (Sun et al., 2005; Oh et al., 2006; Esteban itor of CP-AMPARs, whereas when slices are prepared from 17- et al., 2003). to 21-day-old mice LTP is insensitive to IEM1460 (Sanderson Although LTP of SC-CA1 hippocampal synapses was normal et al., 2016). These findings show that the involvement of CP- in single GluA1 S831A or S845A knockin mice (Lee et al., AMPARs in hippocampal LTP may follow a very narrow develop- 2010), synaptic potentiation at other synapses was found to be mental window of only a few days. Another study has found that sensitive to mutations at either of these sites. Serotonin and se- CP-AMPARs are present at excitatory synapses on cortical layer lective-serotonin reuptake inhibitor type anti-depressants V neurons in mice during their active phase at night, but that (SSRIs) increase the phosphorylation of GluA1 S831 and induce these CP-AMPARs are removed during the sleep phase during synaptic potentiation in the hippocampal CA1 temporoammonic the day (Lante´ et al., 2011). As the majority of research is done pathway. This potentiation, as well as the effects of SSRIs, are during the light phase, when CP-AMPARs are less prevalent, absent in the GluA1 S831A mice (Cai et al., 2013), while ketamine this finding suggests that some of the controversy regarding treatment, which is being developed as a rapid-acting anti- CP-AMPARs may also be subject to time of day effects. depressant, requires phosphorylation of GluA1 S845 for its effect While the importance of the GluA1 C-terminal tail and its PTMs (Zhang et al., 2016). Neuromodulator-mediated spike-timing- in LTP has been questioned by molecular replacement studies dependent LTP in layer IV to II/III synapses in the visual cortex using C-terminal deletions of GluA1 and GluA2 (Granger et al., and the expression of network LTP in the anterior cingulate cor- 2013), recent data from Zhou et al. provide strong evidence tex (ACC) is absent in the GluA1 S845A knockin mice (Song et al., that the GluA1 C-terminal tail is both necessary and sufficient 2017; Seol et al., 2007). Thus, while phosphorylation of GluA1 for hippocampal LTP (Zhou et al., 2018). In this study, the authors S831 or S845 are clearly involved in LTP, the strict requirement generated mouse lines in which the endogenous C-tail of GluA1 for each site as well as the synergistic effects of dual phosphor- was replaced with the C-tail of GluA2: GluA1C2KI, or vice versa: ylation are likely synapse and induction specific. GluA2C1KI. Basal synaptic transmission was completely unal- Other PTMs of GluA1 have also been implicated in LTP, but tered in these mutant mice, unlike previously studied genetic these have not been systematically studied. S-nitrosylation of manipulations of AMPAR subunits (Lu et al., 2009). Importantly, GluA1 C875 by nNOS was found to enhance the phosphorylation LTP was completely absent in GluA1C2KI mice, demonstrating of GluA1 S831 by CaMKII (Figure 1) (Selvakumar et al., 2013), that the GluA1 C-tail is necessary for LTP. In support of this suggesting an additional synergistic relationship between S831 conclusion, GluA2C1KI mice, which express extra copies of the phosphorylation and C875 nitrosylation. The first intracellular GluA1 C-tail, showed enhanced LTP. Incredibly, LTP was loop of GluA1 can be phosphorylated by casein kinase IIb at rescued in GluA1C2KI and GluA2C1KI double-mutant mice, S579 to promote surface targeting (Lussier et al., 2014), and showing that the C-tail of GluA1 is sufficient for LTP expression, GluA1 S863 was found to be a target for PAK3, which promotes even when it is attached to the GluA2 subunit (Zhou et al., 2018). targeting of GluA1 to the cell surface by relieving an unidentified The differences in the findings of the Granger et al. and the Zhou intracellular retention interaction (Hussain et al., 2015). However, et al. studies may be due to the techniques used. In the Granger whether these GluA1 PTMs play a role in LTP remains to be et al. study, AMPAR GluA1–GluA3 subunits were conditionally determined. Neuronal activity can also induce ubiquitination of eliminated during development and replaced with AMPA recep- AMPARs (Widagdo et al., 2015), although the role of this AMPAR tors lacking the C-terminal tails. This method would dramatically PTM in LTP is unknown. Interestingly, ubiquitination and phos- disrupt the composition of synapses and may not reflect the phorylation of GluA1 reciprocally inhibit each other, indicating physiological mechanisms underlying LTP expression (Sheng that a complex crosstalk of GluA1 PTMs may regulate LTP et al., 2013). In contrast, the Zhou et al. study used a more subtle expression (Guntupalli et al., 2017). Signaling from NMDARs approach by generating knockin mutations in the C-terminal tails

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of GluA1, and these experiments, in addition to the GluA1 phos- that GluA3-containing receptors are mostly inert under basal phorylation site knockin experiments described above, likely conditions due to a very low open probability, although these re- reveal the critical role of the GluA1 C-terminal tails in LTP. ceptors are robustly targeted to synapses (Renner et al., 2017). A While much of the work described above has focused on the recent proteomics study has even found that GluA3 subunits are role of GluA1 C-terminal tails, recent studies have identified an the most enriched within the PSD under basal conditions (Pan- important role for the GluA1 amino-terminal domain (Figure 1A) dya et al., 2017). Therefore, synaptic potentiation through in synaptic trafficking and plasticity. The amino-terminal domain GluA3 may not require AMPAR trafficking, but rather cAMP- is highly divergent between AMPAR subunits with 56% iden- dependent enhancement of channel open probability of GluA3- tity. Data show that the amino-terminal domain is not necessary containing receptors already localized to synapses, allowing for the formation of functional ion channels, or delivery onto the for very rapid changes in synaptic efficacy. Whether this mech- cell surface, but is required for targeting and retention of GluA1 at anism contributes to forms of hippocampal LTP remains to be synapses during LTP (Watson et al., 2017; Dı´az-Alonso et al., determined. 2017). Interestingly, these recent studies support earlier models GluA4 and LTP describing the activity-dependent synapse recruitment of GluA1 GluA4 is expressed broadly in neurons early in life and may have versus the constitutive synapse recruitment of GluA2 (Shi et al., unique plasticity rules relevant for synapse maturation and syn- 2001), although not via the earlier described long versus short apse un-silencing (Zhu et al., 2000). GluA4 S842 is phosphory- cytoplasmic tails. lated by PKA (Esteban et al., 2003). Unlike GluA1 where the GluA2/3 and LTP activity of PKA and CaMKII are coordinated for synaptic recruit- While the majority of the literature supports a clear role for GluA1 ment, PKA phosphorylation of GluA4 alone is sufficient for syn- in LTP, GluA2/GluA3 also participate. Earlier models of AMPAR apse delivery and retention (Esteban et al., 2003). The period trafficking suggested that long-tailed AMPARs (GluA1) are of early postnatal life when GluA4 is expressed also coincides rapidly recruited to synapses during LTP, while short-tailed with a period where PKA, and not CaMKII, is required for hippo- AMPARs (GluA2/GluA3) are recruited to synapses in a constitu- campal LTP (Yasuda et al., 2003). The fast kinetics of GluA4 tive manner and gradually replace GluA1-containing receptors at assist in the processing of auditory information (von Gersdorff potentiated synapses (Shi et al., 2001). This subunit exchange and Borst, 2002; Sanchez et al., 2010). The presence of synaptic that occurs following LTP has been suggested as an important GluA4 in these auditory centers could have interesting implica- component in memory consolidation. LTP in the mature hippo- tions for the types and extent of synaptic plasticity at these syn- campus is mediated by GluA2-containing receptors (Adesnik apses. GluA4 clustering at excitatory synapses, particularly onto and Nicoll, 2007). GluA2 and GluA3 form direct protein interac- parvalbumin-positive interneurons, is mediated by the extracel- tions with GRIP1/GRIP2 and PICK1 through their PDZ domains lular neuronal pentraxins, which bind to the extracellular amino (Anggono and Huganir, 2012), which facilitate interactions with terminal domain, again highlighting the role of extracellular inter- additional proteins including KIBRA, Grasp1, and NEEP21, form- actions in AMPAR synaptic recruitment (Pelkey et al., 2015; ing a larger complex involved in AMPAR trafficking (Anggono O’Brien et al., 1999; Sia et al., 2007). and Huganir, 2012). Mice lacking PICK1, KIBRA, or Grasp1 all To summarize, LTP requires an enhancement of synaptic show reductions in hippocampal LTP as well as defects in hippo- AMPARs (Huganir and Nicoll, 2013). The threshold and nature campus-dependent learning and memory tasks (Makuch et al., of induction as well as the magnitude and stability of LTP is 2011; Volk et al., 2010; Chiu et al., 2017 ), and disruption of the therefore the product of the types of AMPARs that are available GRIP1-NEEP21 interaction also impairs LTP (Alberi et al., for synaptic recruitment. The AMPAR code proposes that a hier- 2005; Steiner et al., 2005). An emerging theme from these archy exists for the selective incorporation of AMPAR subunit/ studies suggests that endosomal pools of GluA2 or GluA3, PTM combinations, such that each form of LTP will favor the possibly in the form of GluA1-containing heteromeric receptors, recruitment of specific AMPAR types (Figure 2). Spike-timing are mobilized to the cell surface to facilitate LTP. Another parallel and noradrenaline-dependent LTP in the cortex, for example, mechanism suggests that PICK1 is important during the early will preferentially recruit phosphorylated S845 GluA1-containing phase of LTP where it acts to sequester GluA2-containing receptors (Seol et al., 2007). Hippocampal LTP in very young receptors within endosomes, enabling CP-AMPARs to be tran- neurons may preferentially recruit CP-AMPARs (Plant et al., siently incorporated into synapses ( Jaafari et al., 2012; Clem 2006; Sanderson et al., 2016). We propose that all forms of et al., 2010). LTP will show a hierarchy of AMPAR recruitment. As described GluA3 and LTP above, LTP has been shown to occur in the absence of certain Recently, it has been found that LTP in cerebellar Purkinje AMPAR subunits (Granger et al., 2013). Our proposed hierarchy neurons as well as cerebellar-dependent adaptation of the ves- suggests that in the absence of preferred AMPAR variants, less- tibulo-ocular reflex both depend on GluA3- but not GluA1-con- preferred variants, or even kainate receptors, may substitute, taining AMPARs (Gutierrez-Castellanos et al., 2017). This form although this is may be the case for only the most robust LTP in- of cerebellar LTP does not appear to involve trafficking of duction protocols (Granger et al., 2013). GluA3, but rather relies on an increase in the open probability of GluA3-containing receptors through a cAMP-dependent The AMPAR Code and LTD pathway (Gutierrez-Castellanos et al., 2017). This regulation of GluA2/3 GluA3-mediated transmission has also been observed in hippo- Several major forms of LTD described in the brain including, campal CA1 neurons (Renner et al., 2017). Here it was shown cerebellar LTD and NMDAR-dependent and mGluR-dependent

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AMPAR hierarchy and PSD slots Figure 2. The AMPAR Hierarchy and PSD Slot Hypothesis (A and B) During synaptic plasticity AMPARs are A B LTP LTD GluA1 homomer added or subtracted from PSD/extracellular slots -recruitment may be (A), which are modified in number and/or in their

highly conditional

t affinity for AMPARs during plasticity (B). Traf- s r P i GluA1-containing dual- ficking AMPARs then populate these PSD slots f T

L d P phosphorylated S831/S845 in a hierarchy based on their (i) affinity for the e g P t i n PSD slots and (ii) mobilization and mobility on i u r

r GluA1-containing u the cell surface. AMPARs enter the PSD slots c d e mono-phosphorylated r P through lateral diffusion from extra-synaptic GluA1-containing pools of surface receptors. During LTP, surface -rapidly mobilized through pools are locally enriched with GluA1-containing

activity-depedent trafficking AMPARs through activity-dependent exocytosis, t s r D

i whereas during LTD surface AMPARs are locally f

T GluA2-containing extracellular slot? L

d depleted through endocytosis of GluA2-contain-

e g

v ing receptors. n GluA2/3 i o r -targeted to synapses through u m d e constitutive trafficking r GluA2/3 phosphorylated S880 -promotes interaction with intracellular slot affinity slots added P PICK1 and endocytosis for AMPARs altered or subtracted tyrosine kinases (Hayashi and Huganir, 2004). GluA3 is also tyrosine-phosphory- lated at the homologous site Y881 (R.L.H., unpublished data). Glutamate re- LTD, are expressed by a decrease in synaptic AMPAR content ceptor agonists, including glutamate, AMPA, and NMDA, induce (Huganir and Nicoll, 2013). AMPARs must be removed from the GluA2 tyrosine phosphorylation, which disrupts the interaction PSD, allowing for lateral diffusion away from the synapse, and between GluA2 and GRIP1/GRIP2, but not PICK1 (Hayashi and concomitantly, AMPARs are locally depleted from the cell sur- Huganir, 2004). Multiple studies have shown both in slice phys- face by clathrin- and dynamin-dependent endocytosis (Shep- iology experiments and in vivo that treatment with a short pep- herd and Huganir, 2007). tide mimicking the tyrosine-rich region of GluA2 (called the 3Y GluA2 plays a prominent role in LTD. Several studies have peptide) completely blocks LTD as well as activity-dependent demonstrated that GluA2 is required for the expression of cere- GluA2 endocytosis (Fox et al., 2007; Ahmadian et al., 2004), bellar LTD. Specifically, phosphorylation of GluA2 S880 is while having no effect on basal synaptic transmission. Interest- required as knockin mutations that prevent phosphorylation of ingly, hippocampal mGluR-mediated LTD involves the dephos- this site in mice (GluA2 K882A) eliminate cerebellar LTD (Chung phorylation of GluA2 Y876 and is completely blocked by et al., 2000; Steinberg et al., 2006). This effect of S880 on LTD is inhibitors of tyrosine phosphatases (Moult et al., 2006; Gladding likely mediated by regulating the interaction of GluA2 with the et al., 2009). BRAG2, an Arf6 guanine nucleotide exchange factor PDZ domain containing proteins, GRIP1/GRIP2 and PICK1 that (GEF), has been shown to bind to the GluA2 Y-rich region (Scholz regulate AMPAR membrane trafficking (see below). Consistent et al., 2010). During hippocampal mGluR-LTD, concomitant with this model, genetic deletion of GRIP1/GRIP2 or PICK1 elim- ligand binding and dephosphorylation of GluA2 Y876 stimulates inates cerebellar LTD (Takamiya et al., 2008; Steinberg et al., BRAG2 GEF activity, leading to activation of Arf6 driving GluA2 2006). The GluA2 S880 phosphorylation site has also been endocytosis (Scholz et al., 2010). BRAG2 is also required for shown to be important in hippocampal LTD (Seidenman et al., NMDAR-LTD, but likely through a distinct mechanism as 2003; Chung et al., 2000; Steinberg et al., 2006). These studies NMDAR-LTD does not appear to involve GluA2 Y876 dephos- support a model where GRIP1/GRIP2 bind directly to the PDZ phorylation (Moult et al., 2006), which is required for BRAG2 ligand in the GluA2/GluA3 C-terminal tail, anchoring the recep- GEF activity (Scholz et al., 2010). In cerebellar Purkinje neurons, tors in the PSD (Anggono and Huganir, 2012). Phosphorylation phosphorylation of GluA2 Y876 has been shown to inhibit subse- of GluA2 S880 prevents GRIP1/GRIP2 binding and promotes quent phosphorylation of GluA2 S880 (Figure 1) (Kohda et al., the interaction of the GluA2 PDZ ligand with PICK1 (Seidenman 2013). Dephosphorylation of GluA2 Y876 by tyrosine phospha- et al., 2003; Chung et al., 2000; Steinberg et al., 2006 ), destabi- tase PTPMEG was necessary for S880 phosphorylation and lizing GluA2 within the PSD and promoting GluA2 endocytosis. expression of cerebellar LTD (Kohda et al., 2013). It is possible Via its BAR domain, PICK1 can either promote the invagination that phosphorylation of GluA2 Y876 and S880, as well as of the plasma membrane or direct GluA2 to regions of invagina- GluA3 Y881 and S885, might be similarly coordinated during tion where clathrin-mediated endocytosis occurs (Xia et al., NMDAR- or mGluR-LTD in other brain areas, but this remains 2000; Fiuza et al., 2017). This mechanism likely also applies to to be determined. GluA3, which also interacts with GRIP1/GRIP2 and PICK, and GluA2 is also a target of ubiquitination on K870 and K882, the phosphorylation site, S885, is conserved with GluA2 S880 which occurs in response to neuronal activity and is dependent (Figure 1B). on AMPAR internalization (Widagdo et al., 2015). Although the Several studies have also implicated tyrosine phosphorylation target site of ubiquitination of GluA3 was not identified, GluA3 of GluA2 in LTD. The GluA2 and GluA3 distal C terminus contains K887 is conserved with GluA2 K882. The ubiquitination sites of a cluster of closely spaced tyrosine residues (3 in GluA2 and 4 in GluA2 (and likely GluA3) are very close the Y876/S880 phosphor- GluA3). GluA2 Y876 has been identified as a target for Src family ylation sites (Figures 1B and 1C). However, whether these PTMs

320 Neuron 100, October 24, 2018 Neuron Review

are coordinated has not been determined. Further, the role of to reduce ion-channel properties for expression of LTD (Banke AMPAR ubiquitination in LTD remains to be determined. et al., 2000; Jenkins et al., 2014). Zhou et al. have recently reported that knockin mice in which To summarize, LTD requires a net removal of AMPARs from the GluA2 C-tail is replaced with the GluA1 C-tail: GluA2C1KI are the postsynaptic membrane. In the context of the AMPAR completely impaired in hippocampal NMDAR-dependent LTD code, we propose that at synapses that contain mixed AMPAR (Zhou et al., 2018). NMDAR-LTD can be rescued in the subunits and PTMs, a hierarchy exists such that certain GluA1C2KI/GluA2C1KI double mutants, showing that the GluA2 AMPAR variants will be disproportionally targeted for removal C-tail is both necessary and sufficient for hippocampal during LTD; for example, GluA2/GluA3 containing receptors NMDAR-LTD. Interestingly, in this study, mGluR-dependent phosphorylated at S880 (Figure 2). Hippocampal LTD is still LTD was not affected by the GluA1/GluA2 C-tail exchange. observed in knockouts of GluA2/GluA3 (Meng et al., 2003), but GluA1 not in neurons expressing GluA2 fused to the GluA1 C-tail While the literature on LTD indicates a dominant role of the GluA2 (Zhou et al., 2018). Again, these findings suggest that synaptic subunit, GluA1 has also been shown to be important. GluA1 plasticity is modulated by regulatory elements with the AMPAR S845 dephosphorylation is critical for hippocampal LTD, as the C-tails, but this regulation is circumvented in the absence of GluA1 S845A mutation results in impaired LTD (Lee et al., AMPAR subunits. 2003, 2010), indicating that the induction of LTD requires PKA phosphorylation of GluA1 even though receptors are eventually AMPAR Code and Homeostatic Scaling up dephosphorylated (Huganir and Nicoll, 2013). In hippocampal GluA1 CA1 neurons, synaptic levels of CP-AMPARs are low. However, In response to chronic hyperactivity or hypoactivity, neurons can blocking glutamate re-uptake and causing glutamate spillover engage homeostatic scaling down or scaling up, respectively, in reveals a population of CP-AMPARs in the perisynaptic region, which the strength of excitatory synapses on a neuron is globally which is completely abolished by GluA1 S845A mutation ( He modified to maintain neuronal activity in a physiological range et al., 2009). It has been shown recently that this population of (O’Brien et al., 1998; Turrigiano et al., 1998; Turrigiano, 2008). perisynaptic CP-AMPARs (GluA1 homomers) are transiently Similar to LTP and LTD, synaptic strength is altered during ho- recruited to the synapse during the induction of LTD in a meostatic scaling by changing the abundance of postsynaptic PKA-dependent manner (Sanderson et al., 2016). During the AMPARs (O’Brien et al., 1998). Homeostatic scaling involves induction phase of LTD, transient signaling from synaptic CP- changes in AMPAR protein expression, subunit composition, AMPARs is required for the full expression of LTD, and during protein interactions, and PTMs. TTX-induced homeostatic the progression of LTD induction these CP-AMPARs signal scaling up in cultured neurons increases GluA1 protein expres- their own removal through activation of calcineurin (CaN) (Sand- sion as well as surface and synaptic levels of CP-AMPARs erson et al., 2016). If PKA is not able to phosphorylate GluA1 (GluA1 homomers) and GluA1/GluA2 heteromers but not in S845, CP-AMPAR recruitment to synapses during LTD is GluA3-containing AMPARs (Figure 3) (Diering et al., 2014; blocked, possibly explaining the complete absence of LTD in Soares et al., 2013; Tan et al., 2015; Kim and Ziff, 2014; Hu GluA1 S845A knockin mice. AKAP5 (also called AKAP79/ et al., 2010). Scaling up involves an increase in phosphorylation AKAP150) is a signaling scaffold protein required for LTD of GluA1 S845, but not S831, and is completely blocked in neu- (Sanderson et al., 2016; Jurado et al., 2010). AKAP5 anchors rons with GluA1 S845A knockin mutations but remains intact in both PKA and CaN to GluA1, allowing for the efficient coordina- GluA1 S831A mutant neurons (Diering et al., 2014; Kim and tion of these signaling pathways during LTD (Sanderson and Ziff, 2014 ). Interestingly, during scaling up, the overall PKA activ- Dell’Acqua, 2011). ity in neurons is reduced. GluA1 S845 phosphorylation is A phosphorylation site was identified in the first intracellular increased by a coordinated recruitment of the remaining active loop of GluA1 (S567), which is phosphorylated by CaMKII and PKA into synapses by the signaling scaffold protein AKAP5, promotes removal of GluA1 from synapses (Lu et al., 2010; Coul- and the simultaneous suppression of CaN activity (Figure 3) trap et al., 2014). CaMKII is well known to be required for LTP, but (Diering et al., 2014; Kim and Ziff, 2014). In the GluA1 S845A its activity is also required during LTD where a prolonged ‘‘weak’’ knockin neurons, TTX still induces an increased expression of stimulus favors the phosphorylation of GluA1 S567 over S831, GluA1 protein, but this is insufficient to drive scaling up without leading to removal of synaptic GluA1 (Coultrap et al., 2014). the phosphorylation-dependent recruitment of GluA1 into syn- GluA1 undergoes dephosphorylation of T840 and S845 during apses (Diering et al., 2014). Homeostatic scaling up has also LTD by protein phosphatases PP1/PP2A and CaN, respectively been observed in the visual cortex in mice in response to visual (Delgado et al., 2007; Toda and Huganir, 2015; Lee et al., 1998; deprivation and involves the recruitment of synaptic CP- Sanderson et al., 2016). Under basal conditions, approximately AMPARs and increased GluA1 S845 phosphorylation (Goel 50% of GluA1 is phosphorylated at T840 and acute inhibition et al., 2006; Goel et al., 2011). Like in cultured neurons, visual of PP1/PP2A results in very rapid increases in T840 phosphory- deprivation-induced scaling up is absent in GluA1 S845A lation, suggesting that this site undergoes rapid and regulated knockin mutant mice (Goel et al., 2011). cycling between phosphorylation states (Babiec et al., 2016; GluA2 Lee et al., 2007). GluA1 T840 phosphorylation has been shown While many studies highlight a role of GluA1 in homeostatic to increase GluA1 single-channel conductance while phosphor- scaling up, GluA2 and its direct binding partners, GRIP1/ ylation of S845 increases channel open probability, suggesting GRIP2 and PICK1, also play key roles. Scaling up can be blocked that dephosphorylation of these sites might also be important by the expression of the soluble cytosolic C-terminal tail of GluA2

Neuron 100, October 24, 2018 321 Neuron Review

A inactivity induced scaling-up Figure 3. Subunit-Specific Mechanisms of Homeostatic Scaling (A and B) Schematics of known mechanisms of homeostatic scaling up (A) and scaling down (B) based on GluA1 or GluA2/GluA3.

P P P P P

PKA and AKAP5 -PKA phosphorylation of GluA1 S845 up appears to involve increased tyrosine recruited to PSD -recruitment of GluA1/1 and GluA1/2 phosphorylation of GluA2 as a result of AMPARs downregulation of the tyrosine phospha- tase, STEP61 (Figure 3), and scaling up could be blocked by exogenously applied STEP61 (Jang et al., 2015). Prolonged TTX treatment in cultured neurons causes P P P P lysosomal degradation of PICK1, while GRIP1/2 STEP61 deletion of PICK1 enhances mEPSC phosphatase -recruitment of GluA2 contatining recruited amplitude and occludes homeostatic to PSD downregulated AMPARs -increased tyrosine-phosphorylation scaling up, suggesting that decreased ac- PICK1 degraded of GluA2/3 tivity of PICK1 is an important mediator of scaling up (Figure 3) (Anggono et al., 2011). TTX also causes a downregulation B hyperactivity induced scaling-down of total neuronal GRIP1/GRIP2 protein levels but simultaneously causes an in- crease in the targeting of GRIP1/GRIP2 increased AMPAR PSD off-rate to the PSD, which presumably is required for the recruitment of GluA2-containing P receptors (Figure 3) (Tan et al., 2015; Gainey et al., 2015). Consistent with these uncoupling of -decreased phosphorylation of PKA/AKAP5 GluA1 S845 data, deletion of the GRIP1/GRIP2 genes -GluA1 ubiquitination? completely blocks scaling up (Tan et al., 2015). Neither GRIP1/GRIP2 nor PICK1 are required for scaling down (Tan et al., 2015; Anggono et al., 2011). Despite the fact that both GluA1 and GluA2 have P P been implicated in homeostatic scaling increased PP1 and -decreased phosphorylation of up, complete knockout of GluA1 still al- STEP activity GluA2 Y876 and S880 lowed for the scaling up of GluA2/GluA3, accumulation of -GluA2/3 ubiquitination? and complete knockout of GluA2/GluA3 intracellular GRIP1/2 -intracellular GluA2/3 sequestered still allowed for the scaling up of GluA1 (Altimimi and Stellwagen, 2013), suggest- ing that regulatory elements in GluA1/ GluA2 can be circumvented by complete GluA1/1 GluA2/3 GluA1/2 AKAP5 GRIP1/2 removal of these subunits.

AMPAR Code and Homeostatic P phosphorylation PSD PKA PICK1 Scaling down GluA2 Bicuculline-induced scaling down in cultured neurons involves the downregu- or by shRNA-mediated knockdown of GluA2 (Gainey et al., 2009; lation of GluA1/GluA2/GluA3 protein levels as well as reduced Ancona Esselmann et al., 2017). Scaling up can be rescued by synaptic targeting of all AMPAR subunits (Diering et al., 2014; expression of shRNA-resistant WT GluA2, but not by a GluA2 Tan et al., 2015). AMPAR association with the PSD is reduced chimera with the C-tail swapped for GluA1, suggesting that ele- during scaling down by increasing the rate at which AMPARs ments of the GluA2 C terminus are required for scaling up dissociate from the PSD scaffold (Tatavarty et al., 2013). This (Gainey et al., 2009). Interestingly, scaling up can be supported might in part be a result of dephosphorylation of GluA1 S831 by GluA2 with the C terminus from GluA1 when S818 is mutated and S845, and GluA2 S880 and Y876 (Figure 3) (Diering et al., to alanine (GluA2-A1CTD S818A) to mimic the corresponding 2014; Siddoway et al., 2013; Jang et al., 2015). Dephosphoryla- amino acid in GluA2 (Ancona Esselmann et al., 2017). Scaling tion of GluA2 S880 during scaling down is mediated by activation

322 Neuron 100, October 24, 2018 Neuron Review

GluA1 Synaptic GluA1 is dephosphorylated at S831 and S845 during scaling down, and also in the forebrain during sleep (Diering et al., 2014, 2017), which together with other observations sug- P P P gests that homeostatic scaling down occurs across the forebrain during sleep (Diering et al., 2017). Decreased phosphorylation of activation of PKA and S845 during scaling down is not mediated by phosphatase acti- phosphorylation of vation, but rather by a decrease in PKA targeting to the synapse GluA1 S845 through uncoupling with the AKAP5 scaffold, favoring the de- phosphorylated state of GluA1 (Figure 3 ) (Diering et al., 2014). This mechanism of decreasing the phosphorylation of GluA1 S845 is completely distinct from the dephosphorylation medi- ated by acute activation of CaN during LTD (Sanderson et al., 2016). Interestingly, GluA1 that remains phosphorylated is resis- persistant tant to scaling down and the unphosphorylated GluA1-contain- signaling ing receptors are preferentially removed (Figure 4) (Diering after LTP et al., 2014). Bicuculline treatment drives GluA1 ubiquitination of K868 and is likely part of the mechanism leading to downregu- lation of AMPAR protein levels during scaling down (Widagdo et al., 2015; Scudder et al., 2014). It has been shown that phos- phorylated GluA1 S845 is resistant to ubiquitination (Guntupalli et al., 2017), offering a potential mechanism for the differential removal of phosphorylated and unphosphorylated GluA1 during scaling down. P P P One of the most pertinent questions remaining in the study of phospho-S845 homeostatic scaling is to understand how this form of plasticity GluA1 resistant to interacts with Hebbian plasticity. In order for scaling to proceed scaling-down and in restoring or rebalancing neuronal excitability without cata- ubiquitination strophic disruption of memory storage, scaling should be highly sensitive to previous episodes of LTP and LTD. As both ho- meostatic and Hebbian forms of synaptic plasticity involve the trafficking and modification of AMPARs, it is completely impossible for the different plasticity types to occur indepen- Figure 4. Communication between Hebbian and Homeostatic dently. We hypothesize that local forms of Hebbian plasticity Plasticity Based on the AMPAR Code may involve some sustained signaling and modification of AMPARs are modified at synapses that have undergone Hebbian plasticity, for AMPARs, which could influence the expression of subsequent example phosphorylation of GluA1 during LTP. These synapses maintain signaling, which sustains a population of modified receptors. During homeo- global plasticity. Thus, homeostatic scaling may proceed in a static scaling, synapses across the neuron are strengthened or weakened by manner that effects the entire neuron while at the same time adding or subtracting AMPARs, respectively. This global plasticity is modified is locally sensitive to the previous history of individual synap- locally by the population of modified AMPARs that are either resistant or hy- persensitive to homeostatic scaling. This interaction allows global homeostatic ses, allowing neurons to alter their excitability while maintaining plasticity to be sensitive to previous history of Hebbian plasticity. information storage. For example, homeostatic scaling down during sleep should weaken the majority of synapses while re- of phosphatase PP1, through its regulatory protein inhibitor 2 taining the synapses that have undergone LTP while the animal (I-2) (Siddoway et al., 2013), while dephosphorylation of GluA2 was awake (Diering et al., 2017). Indeed, 3D electron micro- Y876 requires an upregulation of STEP61 ( Jang et al., 2015 ). scopy reconstruction of dendritic spines in mouse cortex Dephosphorylation of these two sites enhances the interaction comparing wake and sleep showed that 80% of spines shrink of GluA2 with GRIP1/GRIP2 scaffold proteins (Hayashi and Hu- during sleep in a multiplicative manner as predicted by homeo- ganir, 2004; Chung et al., 2000). Concomitantly, GRIP1 protein static scaling down, whereas the remaining 20% of dendritic is upregulated during scaling down but remains in intracellular spines appear to escape homeostatic scaling down altogether compartments where it may act to sequester internalized (de Vivo et al., 2017). The studies on the role of AMPAR GluA2-containing receptors away from the synapse (Figure 3) phosphorylation during homeostatic scaling suggest that (Tan et al., 2015). Bicuculline treatment stimulates GluA2 ubiqui- removal of AMPARs from synapses during scaling down may tination on K882 (Widagdo et al., 2015), very close to the Y876 follow a hierarchy whereby dephosphorylated receptors are and S880 phosphorylation sites, and AMPAR ubiquitination preferentially removed. Synapses that have undergone LTP has been shown to be required for homeostatic scaling down and maintain some signaling activity and populations of phos- (Scudder et al., 2014). Whether GluA2 ubiquitination and phos- phorylated AMPARs may be protected from scaling down phorylation interact in the context of homeostatic scaling down (Figure 4). Further exploration of the concepts of the AMPAR has not been determined (Figure 1). code will be important to understand the interaction of Hebbian

Neuron 100, October 24, 2018 323 Neuron Review

and homeostatic plasticity as they push and pull on the very GluA1 favors the accumulation of GluA1 at potentiated synap- same postsynaptic AMPARs. ses. During LTD, AMPARs must be removed from the PSD, and this step seems to be tightly coupled to removal of the AMPAR Code and the Postsynaptic Density Slot AMPARs from the plasma membrane through clathrin-depen- Hypothesis dent endocytosis. Block of endocytosis has been shown in A prominent model of synaptic strength posits that the PSD, a many studies to prevent LTD, suggesting that AMPARs must dense network of synaptic scaffolding, adhesion, and cytoskel- be locally depleted from the cell surface, perhaps to prevent etal proteins, contains ‘‘slots’’ that might be occupied by rapid refilling of the PSD slots. GluA2 seems to play an especially AMPARs supplied by lateral diffusion from the perisynaptic re- important role in LTD (Zhou et al., 2018). GluA2 can directly gion (Opazo et al., 2012; Huganir and Nicoll, 2013; Kessels and interact with AP-2 clathrin adaptor complex, which allows Malinow, 2009). Surface-localized AMPARs are supplied by GluA2-containing receptors to be rapidly depleted from the cell exocytosis from pools of intracellular receptors contained within surface (Kastning et al., 2007; Lee et al., 2002). Thus, the ‘‘slot endosomes (Lin et al., 2009; Makino and Malinow, 2009). The hypothesis’’ offers some explanation for the prominent role of concentration of surface, extra-synaptic AMPARs is controlled GluA1 in LTP and of GluA2 in LTD, via the rapid activity-depen- globally and locally by constitutive or activity-dependent exocy- dent mobilization of GluA1-containing receptors onto the cell tosis/endocytosis, respectively. In the plane of the plasma mem- surface during LTP, and the removal of GluA2 containing recep- brane, AMPARs are highly mobile but become trapped in PSD tors from the cell surface during LTD through interactions with slots ( Opazo et al., 2012). AMPARs eventually diffuse out of the AP2 and/or through interactions involving the GluA2 Y-rich motif PSD slots and can then be removed from the cell surface via (Ahmadian et al., 2004; Anggono and Huganir, 2012; Huganir and endocytosis. During synaptic plasticity, the number of PSD slots Nicoll, 2013). may be altered, and/or the affinity of PSD slots for AMPARs Forms of LTP, LTD, and homeostatic scaling have been shown might be changed, such that AMPARs can accumulate in the to be intact in knockout mice of different AMPAR subunits as well PSD during LTP and are removed during LTD (Figure 2). The mo- as in using molecular replacement experiments (Huganir and lecular basis of the slot is typically attributed to intracellular PSD Nicoll, 2013; Granger et al., 2013; Ancona Esselmann et al., scaffold proteins binding to PDZ ligands on AMPARs or auxiliary 2017). Where does this leave the AMPAR code of synaptic plas- subunits (Hayashi et al., 2000; Sheng et al., 2018) but may also ticity? How, for example, is LTD and homeostatic scaling up involve transmembrane, trans-synaptic, or secreted proteins in- blocked in GluA1 S845A knockin mice, while both forms of plas- teracting with the extracellular AMPAR amino-terminal domains, ticity are intact in the complete absence of GluA1 (Lee et al., including the secreted neuronal pentraxins (Watson et al., 2017; 2010; Diering et al., 2014; Altimimi and Stellwagen, 2013; Selcher Dı´az-Alonsoet al., 2017; Sia et al., 2007; O’Brien et al., 1999; Lee et al., 2012)? We propose that through subunit-specific PTMs et al., 2017) (Figure 2). Under basal conditions the number and and protein interactions, layers of regulation are built into the structure of the slots may be highly stable, while in the minutes AMPARs such that each form of synaptic plasticity will result in following LTP/LTD induction, the PSD slots as a whole may be the recruitment or removal of the correct types and number of transiently malleable, not simply added or subtracted, such AMPARs from PSD slots (Zhou et al., 2018). The recently demon- that local AMPAR dynamics become critical. strated subunit-specific roles of AMPAR amino-terminal do- The AMPAR code predicts that under certain conditions the mains may also inform the molecular basis of these synapse PSD slots will have biased affinity toward certain AMPAR vari- slots (Watson et al., 2017; D´ıaz-Alonso et al., 2017; Sia et al., ants, for example phosphorylated GluA1-containing receptors 2007). This recruitment or removal follows a hierarchy, with during noradrenaline facilitated hippocampal LTP (Makino biased trafficking, accumulation, or removal of certain AMPAR et al., 2011; Hu et al., 2007). An alternative, which is not mutually variants (Figure 2). In the case where individual AMPA subunits exclusive, is that occupation of the PSD slots will be heavily influ- are absent, the layers of regulation associated with that subunit enced by the AMPARs that are most readily available on the cell are also removed, and previously unfavorable AMPARs in the surface, likewise favoring certain AMPAR variants (Figure 2). hierarchy for that plasticity type are ‘‘promoted’’ in the ranking, Large packets of GluA1 are inserted into the dendritic shaft allowing for synaptic plasticity to proceed (Granger et al., from intracellular recycling endosomes, containing an estimated 2013) (Figure 2). 50 GluA1-containing receptors, in an activity-dependent manner (Lin et al., 2009; Makino and Malinow, 2009). The majority of Concluding Remarks these GluA1-containing receptors are likely to be GluA1/GluA2 AMPARs play an essential role in the functioning of the brain, and heteromers (Wenthold et al., 1996; Lu et al., 2009). Activity- changes in the abundance of postsynaptic AMPARs are a funda- dependent increases in extra-synaptic GluA1 have also been mental mechanism for most forms of synaptic plasticity (Huganir observed in vivo in the mouse barrel cortex in response to and Nicoll, 2013 ). Previously, it was proposed that combinatorial whisker stimulation (Zhang et al., 2015). GluA2-containing re- modifications of histones could regulate chromatin structure and ceptors (likely GluA2/GluA3 heteromers) undergo spontaneous gene expression, considerably expanding the informational con- and constitutive exocytosis, but these events are much smaller, tent of DNA (Jenuwein and Allis, 2001). While the translation of containing an estimated 2–5 receptors (Araki et al., 2010; Gu this ‘‘code’’ is far from complete, the concept has proven to be et al., 2016; Lin et al., 2009). As new PSD slots are formed during very influential in the field of epigenetics (Taverna et al., 2007). LTP, or as existing slots increase their affinity for AMPARs, the The AMPAR code likewise suggests that the informational con- large and localized activity-dependent increase in extra-synaptic tent of synapses will include the combinatorial effects of AMPA

324 Neuron 100, October 24, 2018 Neuron Review

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