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Kittler JT, Moss SJ, editors. The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology. Boca Raton (FL): CRC Press; 2006.

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The Dynamic Synapse: Molecular Methods in Ionotropic Receptor Biology.

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Chapter 14AMPA Receptor Phosphorylation in Synaptic Plasticity: Insights from Knockin Mice



Synaptic plasticity in the brain has been implicated to play a role in major brain functions, including learning and memory, developmental plasticity, recovery after injury and drug addiction. The current understanding of the mechanisms of synaptic plasticity derives from molecular and cellular analysis of long-term potentiation (LTP) and long-term depression (LTD). LTP and LTD are readily elicited from many brain regions with different induction and expression mechanisms. At least two different induction mechanisms for LTP and LTD exist, one that depends on activation of N-methyl-D-aspartate (NMDA) receptors and another that does not. The expression of NMDA receptor-dependent and receptor-independent LTP and LTD seem to have overlapping but different signalling mechanisms [1]. Most of the molecular details on NMDA receptor-dependent LTP and LTD have come from studies in the CA1 region of the hippocampus. At least in this region of the brain, regulation of α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors seems to underlie post-synaptic changes associated with NMDA receptor-dependent LTP and LTD. Especially, evidence exists that changes in AMPA receptor phosphorylation is one of the mechanisms critical for the expression of NMDA receptor-dependent bidirectional synaptic plasticity.

This review will summarize the recent findings from our work using gene “knockin” mice lacking specific phosphorylation sites on the GluR1 subunit of AMPA receptors, and discuss the implications of our results that elucidate the basic mechanisms of NMDA receptor-dependent synaptic plasticity.


Fast excitatory synaptic transmission in the central nervous system (CNS) uses glutamate, which acts on various post-synaptic ionotropic glutamate receptors. Ionotropic glutamate receptors are divided into AMPA receptors, NMDA receptors and kainate receptors depending on their agonist preferences. In most CNS synapses, AMPA receptors mediate the majority of basal synaptic transmission, whereas NMDA receptors are activated under conditions that produce significant post-synaptic depolarization. Kainate receptors can participate in synaptic transmission at certain synapses and are also known to play a modulatory role [2]. AMPA receptors are tetramers comprised of combinatorial assembly of four different subunits GluR1 to GluR4 (or GluR-A to GluR-D) [3–5]. Different subunits show distinct spatial and temporal distribution in the brain and confer distinct properties to the AMPA receptor complexes. For example, the GluR2 subunit prevents Ca2+ permeability of the ion channel and contributes to the linear I–V relationship of the current flux [6–12].

All four subunits of AMPA receptors have several identified phosphorylation sites on their intracellular carboxy terminal [13]. Functions of some of the GluR1 and GluR2 phosphorylation sites have been linked to LTP and LTD. GluR1 phosphorylation at serine-831 (S831) and serine-845 (S845) was shown to change with both LTP and LTD [14–17]. Recently, using mice that specifically lack these two phosphorylation sites, we demonstrated that these two sites are essential for LTP and LTD [18]. We will discuss this result in more detail to suggest a model of how these two phosphorylation sites can contribute to bidirectional synaptic plasticity. As for the GluR2 subunit, phosphorylation at S880 has been implicated in mediating LTD in both cerebellum and in hippocampal CA1 regions [19–21]. Because most AMPA receptors in the hippocampal CA1 are heteromeric complexes of GluR1 and GluR2 [5], interactions between the C-tail phosphorylation sites are likely. We will review data suggesting how these two subunits can interact to regulate LTP and LTD.


The first to promote a specific hypothesis on the modifications of AMPA receptors in synaptic plasticity was Lynch and Baudry (1984). They proposed that an increase in Ca2+ by NMDA receptor activation leads to more functional AMPA receptors at synapses. The predicted increase in the AMPA receptor component of synaptic transmission following LTP has been observed by either using specific antagonists [22–24] or by measuring post-synaptic responsiveness to exogenously applied AMPA receptor agonists [24–26]. An increase in AMPA receptor function could be due to up-regulation of functional synaptic receptors or by modification (i.e., phosphorylation) of existing synaptic receptors and evidence is found to support both mechanisms. Recent studies indicate that the two mechanisms might be interrelated [18,27].

The first convincing demonstration that an increase in the number of functional synaptic receptors occurs comes from Malinow’s group. They found that LTP is associated with an insertion of AMPA receptors to synapses by visualizing GFP-tagged GluR1 subunits [28] and by measuring synaptic responses from “electro-physiologically-tagged” GluR1 homomeric receptors [27,29,30]. Homomeric GluR1 AMPA receptors were functionally delivered to synapses after LTP induction, whereas homomeric GluR2 or GluR3 AMPA receptors were inserted constitutively [29]. Subunit-specific trafficking rules are determined by the intracellular carboxy-tail of each subunit [29], suggesting a role of intracellular interacting proteins that bind the carboxy-tails. Recent evidence supports a model in which the insertion of GluR1-containing receptors occur indirectly via insertion at extrasynaptic sites followed by a lateral movement into the synaptic sites [31,32]. Interesting to note is that some forms of LTP are absent in GluR1 knockout mice [33–35] (but see [36] for further support of a role for GluR1 in LTP).

LTP and LTD are also known to depend on protein kinase and protein phosphatase activity, respectively [1]. Therefore, that changes in phosphorylation of synaptic proteins would mediate the expression of LTP and LTD was suggested early [37,38]. One of the post-synaptic proteins that change phosphorylation state with LTP and LTD is the AMPA receptor. LTP induction increases phosphorylation of GluR1 on serine 831 [14,17], although serine 845 can also increase if LTP is induced following LTD induction [17]. A link between GluR1 phosphorylation and insertion of AMPA receptors into synapses also seems to exist [27,39].

Ample evidence is found that CaMKII is involved in LTP [40,41]; hence, one likely candidate phosphoprotein that could mediate LTP was thought to be GluR1, specifically by phosphorylation on the S831 site [14,17,42]. However, mutating S831 to an alanine does not affect the activity-dependent insertion of GluR1 [30]. Alternately, mutation of GluR1 S845 to an alanine is reported to prevent activity-dependent insertion of GluR1 to synapses [27]. The latter result implies an involvement of protein kinase A (PKA) signalling for GluR1 insertion by LTP-inducing stimulation. As will be discussed later, PKA has been implicated to play a role in LTP; however, the exact role of PKA has been debated. At this moment, the role of S831 in LTP is unclear, except that it could perhaps underlie the increase in conductance of AMPA receptors following LTP [43]. However, whether an increase in AMPA receptor conductance following LTP exists has recently been challenged [44].

As for LTD, evidence exists that it is associated with dephosphorylation of the GluR1 subunit of AMPA receptors [15–17]. The dephosphorylation of AMPA receptors associated with LTD was specific to S845 [15–17]. However, S831 dephosphorylation could also be observed when LTD was followed by LTP induction [17]. As will be discussed later, the dephosphorylation of S845 seems to be one of the mechanisms that lead to removal of synaptic AMPA receptors following LTD induction [18,39], along with GluR2-dependent mechanisms [19,45–53].


Recently, we provided further evidence that GluR1 S831 and S845 phosphorylation sites are indeed involved in LTP using mutant mice specifically lacking the two phosphorylation sites [18]. These mice were generated in Huganir’s laboratory by replacing the genomic GluR1 sequence with a targeting vector construct that has both S831 and S845 mutated to alanines. We found that LTP is still present in the GluR1 phosphomutants; however, the magnitude was less than that from wild-type littermates. This result contrasts with the GluR1 knockout mice data, where LTP induced with tetanus is absent [33,35]. Collectively, this data indicates that at least two mechanisms for LTP expression exist, one that depends on GluR1 and the other that requires phosphorylation of this subunit. This data supports a model in which GluR1 insertion occurs upon LTP induction, after which the subunits are phosphorylated, allowing for stable incorporation at synapses (Figure 14.1).

FIGURE 14.1. A proposed mechanism of LTP.


A proposed mechanism of LTP. (a) Extrapolation of LTP data from adult GluR1 double phosphomutants. Exponential decay curves were fit on average LTP data from wild-types and GluR1 double phosphomutant homozygotes. Note that the decay time constant (t) (more...)

Stabilization of newly inserted GluR1 is thought to depend on its attachment to post-synaptic density (PSD) proteins. A specific hypothesis put forth by Lisman proposed that activation of NMDA receptors upon LTP leads to autophosphorylation of CaMKII, which then binds the intracellular C-tail of NMDA receptors at the PSD [54]. These CaMKII molecules then act to recruit “slot” proteins for AMPA receptor insertion. An attractive candidate that can serve as a “slot” protein is a member of a membrane-associated guanylate kinase (MAGUK) family protein, SAP97 [54]. SAP97 was shown to indeed interact with the extreme GluR1 C-tail, which has a type I PDZ ligand motif (TGL) [55–57]. SAP97 is known to interact with the intracellular population of AMPA receptors [58]; however, it is also co-localized at PSDs together with GluR1 [59]. CaMKII phosphorylation of SAP97 seems to allow it to move into spines [60]. Therefore, SAP97 is a likely candidate that can mediate CaMKII-dependent insertion of AMPA receptors to synapses. In support of this, mutation of the GluR1 PDZ ligand (TGL to AGL) that disrupts its interaction with SAP97 prevents activity-dependent insertion of homomeric GluR1 AMPA receptors [30]. Furthermore, over-expression of SAP97 increases AMPA receptor-mediated miniature post-synaptic currents (mEPSCs) [61]. Therefore, insertion of GluR1-containing AMPA receptors upon LTP seems to depend on the GluR1 interaction with PDZ proteins, a likely candidate being SAP97.

Interestingly, SAP97 interacts directly with AKAP79/150, which brings PKA in close proximity to the GluR1-containing AMPA receptor complexes [56]. In addition, the formation of this GluR1-SAP97-AKAP complex significantly increases phosphorylation of GluR1 at S845 [56,62]. This result provides an attractive molecular mechanism in which phosphorylation may stabilize synaptic GluR1. We propose the following model for LTP induction, which is based on a model suggested by Lisman’s group [40,54] and on our interpretation of the data from the GluR1 phosphomutants. We surmise that LTP induction produces “slots” for GluR1-containing AMPA receptor insertion to synapses. A recent study suggests that the insertion happens from AMPA receptors on recycling endosomes [63]. CaMKII-dependent phosphorylation of SAP97 can traffic these intracellular pools of AMPA receptors to the PSD. The newly inserted AMPA receptors are then phosphorylated at S845 by the recruitment of AKAP79/150 by SAP97. The S845 phosphorylation in turn can stabilize the GluR1-containing AMPA receptors at the PSD.

Our model predicts that synaptic GluR1 are highly phosphorylated at S845 under basal conditions. Consistent with this idea, PKA activation does not enhance basal synaptic AMPA receptor function [15,64,65]. In contrast, application of a PKA inhibitory peptide (PKI) depresses synaptic AMPA receptor responses [15]. Moreover, GluR1 subunits isolated from the PSD cannot undergo further phosphorylation by PKA [66], despite the fact that when looking at the total pool of GluR1, PKA activation can greatly increase S845 phosphorylation [16,67–69]. Collectively, this data suggests that the synaptic AMPA receptors could be already fully phosphorylated at the PKA site, and the maintenance of their phosphorylation requires an ongoing PKA activity. Our hypothesis is that the ongoing PKA activity is provided by the recruitment of PKA by GluR1-SAP97-AKAP complex formation at synapses. In support of this, post-synaptic injection of inhibitory peptide that prevents PKA binding to AKAP causes a “run down” of synaptic AMPA receptor-mediated currents [62,64]. The stability of phosphorylated AMPA receptors at synaptic locations can be interpolated from reports that dephosphorylation of GluR1 S845 is associated with an increase in receptor internalization [18,39]. We will discuss this topic in more detail later.


One of the findings from the GluR1 phosphomutants is that the deficit in LTP was only present in adult animals (2 to 3 months of age) and not in young animals (3 to 4 weeks old) [18]. This result is in line with the observation that LTP deficit in GluR1 knockouts are also only seen in adults [33–35], and suggests that a developmental switch exists in the mechanisms of LTP such that it is initially independent of GluR1 and becomes GluR1-dependent. This interpretation is seemingly at odds with a previous study by Malinow’s group showing LTP-dependent GluR1 insertion in “young” organotypic hippocampal slice cultures [28–30]. However, the difference could be due to the fact that Malinow’s group was transfecting GFP-tagged GluR1, which forms homomeric receptors. Thus, the discrepancy might shed light on additional regulatory mechanisms in native heteromeric AMPA receptor complexes.

Developmental changes in LTP mechanisms are well-documented [70–74]. A wealth of evidence is found that LTP in mature animals require CaMKII activity [74–76]. However, in neonates (P7-8), LTP is not dependent on CaMKII but on PKA activity [73]. Interestingly, around the second week of postnatal age, LTP is shown to depend on concurrent activation of CaMKII and PKA or CaMKII and PKC [72]. These results indicate that the protein kinase activity required for LTP changes during postnatal development.

At the level of AMPA receptors, the expression of different subunits show distinct temporal patterns during development. For instance, GluR1, GluR2 and GluR3 subunits show a gradual increase in protein level during postnatal development, whereas the GluR4 subunit is expressed at a high level during the early postnatal week and gradually diminish over time [35,71]. In addition, a minor isoform of GluR2, which has a long C-tail (GluR2long), shows a peak expression level between the first and second postnatal week [70]. Because different subunits and splice variants confer distinct properties on AMPA receptor function and trafficking, the mechanisms of regulation will likely change depending on the subunit composition of synaptic AMPA receptors. In accordance with this fact, recent data suggests that in neonates, spontaneous activity can deliver homomeric GluR4 receptors to synapses, which is dependent on the phosphorylation of a PKA site (S842) [27]. However, the synaptic delivery of GluR4 homomeric AMPA receptors is absent when the animals are older than P10 [70,71]. Coincidentally, the insertion of GluR2long into synapses is shown to account for at least 50% of the potentiation following LTP induction between the first and second postnatal week [70]. Therefore, GluR4- and GluR2long-dependent mechanisms likely play a dominant role in LTP expression in young animals. As the expression level of GluR1 and α-CaMKII increases as the animals mature, LTP then becomes more dependent on these two molecules.


The role of PKA in adult LTP has been mainly restricted to the late phase LTP (L-LTP). Initial studies using bath application of PKA inhibitors showed that only the late maintenance phase of LTP (3 hours or more after induction) is blocked [77,78]. These results led to the conclusion that the early phase of LTP is independent of PKA activity. However, studies exist demonstrating that even the early phase of LTP (less than 1 hour after induction) could be inhibited by PKA inhibitors [65,79,80]. In any case, the effect of PKA inhibitors on LTP, whether the inhibition occurs earlier or later, seems to be by affecting the stability of potentiation: LTP is initially induced to a normal magnitude but fails to stabilize. The interpretation of the role of PKA in LTP has been that it acts to “gate” plasticity by counteracting protein phosphatase activity [65,80,81].

Another line of evidence supporting the involvement of PKA in LTP comes from studies using drugs to increase intracellular cAMP levels. Increasing intracellular cAMP with either activators of adenylyl cyclase or cAMP analogs produces synaptic potentiation, which is long-lasting [82–84]. Recently, a chemical method to induce LTP was developed using a cocktail of drugs aimed at increasing intracellular cAMP levels [85]. Evidence is also found that a transient increase in PKA activity exists following LTP induction [86]. Because the increase in PKA activity was transient, PKA likely triggers a cascade of events leading to stabilization of LTP. According to our model, one of the molecules that could mediate the stability of LTP is AMPA receptor via its phosphorylation of GluR1 on the S845 site.


LTD is associated with a dephosphorylation of GluR1 S845 [15–17], and this was subsequently shown to be necessary for LTD [18]. The role of GluR1 phosphorylation sites in LTD is probably by mediating AMPA receptor internalization upon dephosphorylation [18,39].

LTD has long been shown to depend on the activity of various protein phosphatases [87,88]. In addition, LTD is known to dephosphorylate a post-synaptic PKA substrate [15], one of which is GluR1 on S845 [15–18]. The dephosphorylation of GluR1 S845 is likely mediated by a protein phosphatase cascade involving protein phosphatase-1 (PP1) and calcineurin (PP2B) [16,17]. Both PP1 and PP2B are localized to post-synaptic sites via interacting molecules [89,90], which brings them in close vicinity to possible synaptic substrates, including AMPA receptors. Synaptic localization of protein phosphatases is critical for LTD because disrupting the interaction between protein phosphatases and their synaptic anchors prevent LTD [91].

Dephosphorylation of GluR1 S845 following LTD induction can be studied biochemically using a chemical method for inducing LTD (ChemLTD) [15,16]. Using this chemLTD method, GluR1 S845 dephosphorylation was shown to be linked to the internalization of synaptic AMPA receptors [18]. chemLTD-induced internalization of AMPA receptors was absent in mice lacking both S831 and S845 phosphorylation sites, indicating that the phosphorylation sites are critical for the activity-dependent internalization [18]. Because chemLTD is associated with a dephosphorylation of the S845 site [15,16,18,92], the interpretation is that this phosphorylation site is critical for AMPA receptor internalization following LTD. In addition, the fate of the internalized AMPA receptors seems to depend on the phosphorylation state of GluR1 S845. For example, dephosphorylation of S845 traffics the internalized receptors to the lysosome for degradation, whereas phosphorylation at this site allows reinsertion into the plasma membrane [39]. Accordingly, persistent dephosphorylation of GluR1 S845, as observed following LTD induction [16,17], could lead to degradation and down-regulation of synaptic AMPA receptors. Indeed, LTD-induced degradation of AMPA receptors has been observed [93].


Despite the evidence linking GluR1 phosphorylation sites and AMPA receptor internalization following LTD [18,39], the majority of studies point to the GluR2 subunit as playing a critical role for activity-dependent AMPA receptor internalization [94]. In addition, a recent study suggests that GluR2 plays a dominant role in determining the fate of AMPA receptors internalized by activity [53]. However, these observations do not preclude a role for GluR1 in either initiating or stabilizing internalized AMPA receptors. Because the majority of synaptic AMPA receptors are heteromers of GluR1 and GluR2 [5], that the two subunits could coordinate the activity-dependent internalization of AMPA receptors is possible.

Activity, either in the form of glutamate receptor agonists or synaptic activation, can internalize AMPA receptors [94]. Activity-dependent internalization of AMPA receptors occur via clathrin-coated pits and require the action of dynamin [49,95,96]. AMPA receptors destined to internalize are targeted to clathrin-coated pits via interacting with a clathrin adaptor protein AP2 [48,49,95]. Although the outcome of different forms of activity leading to AMPA receptor endocytosis is the same, the molecular mechanisms seem to vary [96]. For instance, AMPA receptors internalized by AMPA treatment end up in the lysosomes, whereas NMDA-induced internalization targets internalized AMPA receptors to the recycling endosomes [39,53]. Evidence suggests that activity-dependent internalization of AMPA receptors relies on the interaction of carboxy-terminal tail of GluR2 subunit to several of its binding partners [19,21,46,49,53,96,97].

The GluR2-dependent internalization of AMPA receptors seems to rely on phosphorylation of S880 on the extreme carboxy-terminal, which conforms to a type II PDZ ligand [52,98,99]. Phosphorylation of GluR2 on S880 shifts the balance of GluR2 interaction with GRIP/ABP to Pick-1 [98,99]. Pick-1 was originally identified as protein interacting with PKC [100,101]. Pick-1 is thought to bring PKC into the vicinity of synaptic AMPA receptors [102], probably by its ability to form homodimers [101,103]. Because GluR2 S880 can be phosphorylated by PKC [98,99], Pick-1 is in a position that can mediate increases in GluR2 S880 phosphorylation.

Subsequent studies demonstrated that GluR2 S880 phosphorylation is involved in LTD both in cerebellum [20,104,105] and in hippocampal CA1 [19,21,51]. The role of PKC in cerebellar LTD has been well-characterized [105–109]. Hence, a likely scenario for cerebellar LTD is that its induction leads to PKC activation and recruitment of PKC to synapses via Pick-1, which then phosphorylates GluR2 S880 to mediate endocytosis [20,104,105]. In contrast, hippocampal LTD is associated with a decrease in PKC activity [110,111]. Therefore, that GluR2 S880 is phosphorylated by PKC during LTD is unlikely. The identity of the in vivo protein kinase responsible for phosphorylating GluR2 S880 in the hippocampus is currently unknown.

Although overwhelming evidence exists indicating a critical role of GluR2 for AMPA receptor endocytosis associated with LTD, it is likely not the only mechanism. In support of this idea, knockout mice lacking GluR2 or double knockout of GluR2 and GluR3 still exhibit LTD [112,113]. These results indicate that even in the absence of the GluR2 subunit, LTD can still be expressed, presumably, by the remaining GluR1 subunit. Thus, that two independent mechanisms for LTD expression exist seems plausible: GluR1-dependent and GluR2-dependent. At present, how these two mechanisms would interact with each other is not clear. One possibility is that GluR1 dephosphorylation allows GluR2-dependent receptor internalization to take place (Figure 14.2a). Alternatively, GluR1 dephosphorylation could stabilize or allow degradation of AMPA receptors internalized by GluR2-dependent mechanisms (Figure 14.2b). In either case, both scenarios can explain the observation that GluR1 phosphomutants lack LTD [18] and that blocking GluR2-dependent mechanisms prevent LTD expression [19,21,94]. Although conceptually GluR1 and GluR2 likely interact to mediate LTD, whether this interaction exists in vivo is unclear at this point and awaits further investigation.

FIGURE 14.2. Two alternative mechanisms for LTD.


Two alternative mechanisms for LTD. (a) LTD induction leads to dephosphorylation of GluR1 subunits at S845 sites. This dephosphorylation signals the activation of internalization machinery, which could be mediated by GluR2-dependent mechanisms. Recent (more...)


The use of gene knockin mice lacking specific phosphorylation sites on the GluR1 subunit has provided insights into the molecular mechanisms of LTP and LTD. In addition, it allows testing of the in vivo role of the specific GluR1 phosphorylation sites. One important advantage of using GluR1 phosphomutants is that it allows for a straightforward interpretation of data by directly studying a downstream target of the signalling cascades. In contrast, studies on intermediate signalling molecules (i.e., protein kinases and phosphatases) are limiting because of the pleiotropic nature of their actions. The future use of mice lacking specific phosphorylation sites or residues on AMPA receptors will allow for a more detailed understanding of the molecular mechanisms of bidirectional synaptic plasticity. Especially, further work is needed in understanding how different subunits interact with each other in a heteromeric complex to regulate AMPA receptor function.


The author would like to thank A. Kirkwood for helpful discussions.


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