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Neuropharmacology xxx (2016) 1e10

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Neuropharmacology

journal homepage: www.elsevier .com/locate/neuropharm

Invited review

Forgetting of what was once learned: Exploring the role ofpostsynaptic ionotropic glutamate receptors on memory formation,maintenance, and decay

Ricardo Marcelo Sachser a, c, Josu�e Haubrich b, c, Paula Santana Lunardi a, c,Lucas de Oliveira Alvares a, c, *

a Neurobiology of Memory Lab, Biophysics Department, Bioscience Institute, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazilb Psychobiology and Neurocomputation Lab, Biophysics Department, Bioscience Institute, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grandedo Sul, Brazilc Graduate Program in Neuroscience, Federal University of Rio Grande do Sul, Porto Alegre, Rio Grande do Sul, Brazil

a r t i c l e i n f o

Article history:Received 2 May 2016Received in revised form12 July 2016Accepted 13 July 2016Available online xxx

Keywords:Long-term potentiationGlutamateNMDAAMPADecayDepotentiation

* Corresponding author. Laborat�orio de Neurobiomento de Biofísica, Instituto de Biociencias, UniversidSul (UFRGS), Avenida Bento Gonçalves, 9500, Pr�edio 4970, Porto Alegre, Rio Grande do Sul, Brazil.

E-mail address: lucas.alvares@ufrgs.br (L. de Olive

http://dx.doi.org/10.1016/j.neuropharm.2016.07.0150028-3908/© 2016 Elsevier Ltd. All rights reserved.

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a b s t r a c t

Over the past years, extensive research in experimental cognitive neuroscience has provided acomprehensive understanding about the role of ionotropic glutamate receptor (IGluR)-dependentsignaling underpinning postsynaptic plasticity induced by long-term potentiation (LTP), the leadingcellular basis of long-term memory (LTM). However, despite the fact that iGluR-mediated postsynapticplasticity regulates the formation and persistence of LTP and LTM, here we discuss the state-of-the-artregarding the mechanisms underpinning both LTP and LTM decay. First, we review the crucial rolesthat iGluRs play on memory encoding and stabilization. Second, we discuss the latest findings inforgetting considering hippocampal GluA2-AMPAR trafficking at postsynaptic sites as well as dendriticspine remodeling possibly involved in LTP decay. Third, on the role of retrieving consolidated LTMs, wediscuss the mechanisms involved in memory destabilization that occurs followed reactivation that sharestriking similarities with the neurobiological basis of forgetting. Fourth, since different AMPAR subunitsas well as postsynaptic scaffolding proteins undergo ubiquitination, the ubiquitin-proteasome system(UPS) is discussed in light of memory decay. In conclusion, we provide an integrated overview revealingsome of the mechanisms determining memory forgetting that are mediated by iGluRs.

© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Generating and stabilizing hippocampus-dependent long-term memory: role of iGluRs in LTP induction and memory formation . . . . . . . . . . . . . . . . . 003. Toward the neurobiology of forgetting: role of iGluRs in the active decay of long-lasting memory traces . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. How retrieval affects the fate of long-lasting memory traces? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. Ubiquitin-proteasome system may regulate long-memory maintenance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Concluding remarks and future directions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

logia da Mem�oria, Departa-ade Federal do Rio Grande do3422, Sala 216A, CEP 91.501-

ira Alvares).

R.M., et al., Forgetting of whation, maintenance, and

1. Introduction

It is widely accepted among cognitive psychologists and neu-robiologists that forgetting is one of the most fundamental

at was once learned: Exploring the role of postsynaptic ionotropicdecay, Neuropharmacology (2016), http://dx.doi.org/10.1016/

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attributes of the brain (Hardt et al., 2013; Wixted, 2004). Extensiveresearch has shown that iGluR-mediated signaling plays a crucialrole in regulating LTP and LTM formation (Collingridge et al., 1983;Lynch and Baudry, 1984; Nicoll et al., 1988). However, the under-lying mechanisms mediated by iGluRs such as NMDAR and AMPARupon time-dependent memory loss are only now being elucidated(Hardt et al., 2013; Migues et al., 2016; Sachser et al., 2016;Shinohara and Hata, 2014; Villarreal et al., 2002). Understandingthe cellular and molecular basis implicated in forgetting may shednew light on the development of strategies that might be used inage-related memory loss, or by accelerating forgetting of traumatic,maladaptive long-term memories.

Here we offer an integrative overview regarding the involve-ment of iGluRs on forgetting of what was once learned. First, wereview the crucial roles that iGluRs play on memory encoding andstabilization. Second, we discuss the latest findings in forgettingconsidering hippocampal GluA2-AMPAR trafficking at postsynapticsites as well as dendritic spine remodeling. Third, on the role ofretrieving fully consolidated LTMs, we discuss the mechanismsinvolved in memory destabilization followed by memory reac-tivation that share striking similarities with the neurobiologicalunderpinnings of forgetting. Fourth, since different AMPAR sub-units as well as postsynaptic scaffolding proteins undergo ubiq-uitination, the UPS is discussed in light of memory decay. Finally,given that several signaling cascades initiated by Ca2þ influxthrough GluN2B-NMDAR activation were recently implicated instructural and functional postsynaptic plasticity involved in LTPdecay, we present a hypothetical model attempting to explain howLTMs are forgotten at the cellular and molecular levels.

We will focus our attention on the research data obtained fromrodents in the behavioral, biochemical and electrophysiologicallevels. For further information concerning remarkable break-throughs in different models of forgetting, the reader is invited tocheck such studies elsewheredfrom humans (Gagnepain et al.,2014; Lewis-Peacock and Norman, 2014; Wimber et al., 2015) toinvertebrates like the nematode Caenorhabditis elegans(Hadziselimovic et al., 2014; Inoue et al., 2013) and the fruit flyDrosophila melanogaster (Berry and Davis, 2014; Berry et al., 2015;Davis, 2010). Altogether, ongoing research indicates that specificbiological mechanisms responsible for memory forgetting wereconserved throughout evolution. In the case of the mammalianbrain, particularly focusing on rodents, here we discuss strong ev-idence showing that Ca2þ-dependent signaling through iGluRsseems to play crucial roles controlling decay of hippocampal LTPand LTM.

2. Generating and stabilizing hippocampus-dependent long-term memory: role of iGluRs in LTP induction and memoryformation

What are the initial steps of LTM formation? Decades of inten-sive investigation in experimental neuroscience revealed keymechanisms underpinning synaptic plasticity induced by hippo-campal LTP, the leading cellular basis of LTM. It is well establishedthat postsynaptic iGluRs such as NMDAR and AMPAR play crucialroles in regulating LTP and LTM consolidation, particularly in thehippocampus (Collingridge et al., 1983; Henley et al., 2011; Herringand Nicoll, 2015; Hsieh et al., 2007; Huganir and Nicoll, 2013;Kandel et al., 2014; Lynch and Baudry, 1984; Malenka and Bear,2004; Migues et al., 2010; Morris et al., 1986; Morris, 2013; Nicollet al., 1988; Whitlock et al., 2006). Since the 1980s, it has beenproposed that memory formation requires NMDAR activation byglutamate (Collingridge et al., 1983; Morris et al., 1986) and Ca2þ

influx (Lynch et al., 1983). During learning, glutamate is releasedfrom presynaptic terminals in the hippocampus, acting on NMDARs

Please cite this article in press as: Sachser, R.M., et al., Forgetting of whglutamate receptors on memory formation, maintenance, andj.neuropharm.2016.07.015

and AMPARs. The depolarization caused by Naþ influx throughAMPARs releases the Mg2þ that normally blocks NMDAR, permit-ting Ca2þ entrance. These first events, which follow the LTP in-duction and memory acquisition, induce a series of processesincluding the cytoskeleton rearrangement, AMPAR trafficking, andprotein synthesis. These processes are essential for allowingmemory to persist in a long lasting manner.

Although the question on the specific role of the presynapticversus postsynaptic component in LTP induction remains still open,experiments using uncaged glutamate show that it promotesstructural LTP in dendritic spines in the same magnitude presentedwith presynaptic stimulation (Bosch et al., 2014; Meyer et al., 2014),suggesting that the postsynaptic element plays a prominent role inthe LTP induction. Thus, this review will focus mainly on thepostsynaptic events.

The rapid AMPAR trafficking to the postsynaptic density (PSD)that follows the LTP induction is a critical step that ultimately leadsto the strengthening of synaptic transmission. AMPARs arecomposed of different subunits (GluA1e4). Depending on thesubunits composing the AMPAR, it presents distinct properties.AMPARs containing the GluA2 subunit are Ca2þ impermeable (CI-AMPARs), whereas GluA2-lacking AMPAR are permeable to Ca2þ

(CP-AMPARs). In the brain, most of the GluA2 subunit is found in analternative form, produced by mRNA editing that makes it calciumimpermeable. Moreover, while the GluA2-AMPAR is present in thePSD in basal conditions, the GluA1 subunit-containing AMPAR isintroduced during LTP induction (Herring and Nicoll, 2015).

It is widely accepted that the GluA1-AMPARs are incorporated inthe PSD following LTP induction or memory formation (Henley andWilkinson, 2016; Hu et al., 2007; Malenka and Bear, 2004). In a fewhours, they are gradually substituted by GluA2-containing AMPARsat the synapse (a stable AMPAR form that is more resistant todisruption) (Clem and Huganir, 2010; Hong et al., 2013; Shi et al.,2001).

The post-translational modifications play a crucial role onAMPAR trafficking. GluA1 phosphorylation by multiple kinases(such as PKA, PKC and CaMKII) at different sites (such as Ser 845,831 and 818) increases the delivery and trapping by the stargazin-PSD95 complex in the PSD, as well as its channel biophysicalproperties. On the other hand, GluA1 dephosphorylation by thephosphatase calcineurin at Ser 845 induces GluA1 internalization,weakening synaptic transmission (Beattie et al., 2000). By contrast,GluA2 phosphorylation by PKC at Ser 880 increases the internali-zation rate of AMPAR (Lee et al., 2004; Shi et al., 2001). There areexcellent recent reviews describing the AMPAR trafficking that gobeyond the scope of this review (Henley and Wilkinson, 2016;Huganir and Nicoll, 2013).

It has been proposed that the actin filaments (F-actin) andspectrin close to the plasma membrane in the PSD act as a barrier,blocking the passage of important elements involved in LTP in-duction andmemory formation such as AMPARs and CaMKII (Rudy,2015). Then, in order to permit AMPAR delivery during LTP induc-tion, the cytoskeleton needs to be disassembled (Gu et al., 2010).Following LTP induction or memory formation, there is a rapid Ca2þ

increase in the PSD. The intracellular Ca2þ elevation comes from theNMDAR, the L-type voltage-dependent Ca2þ channels (LVDCCs), orby internal organelles (such as the endoplasmatic reticulum) topromote the activation of several pathways such as PKC, CaMKII, aswell as Rac-PAK and RhoA-ROCK, which in turn regulates LIM ki-nase (LIMK) activity. The Ca2þ also activates the enzyme calpain, aprotease that degrades the cytoskeletal protein spectrin, promotingan increase in AMPAR levels in the PSD by opening the actinnetwork (Lynch et al., 2007, 1982). Indeed, the pharmacologicalinhibition of calpain (Oliver et al., 1989), in addition to the condi-tional downregulation (Amini et al., 2013), prevents LTP induction.

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Then, the spine head cytoskeleton is rebuilt in an expandedconfiguration: the LIMK-cofilin phosphorylation by both Rac-PAK-and RhoA-ROCK-dependent cascades (Rex et al., 2009) induce anincrease of the spine growth through new F-actin polymerization.In fact, by using two-photon glutamate uncaging technique thatallows the visualization of the protein translocation in response tostimuli in real time, Bosch and colleagues demonstrated that LTPtriggers spine enlargement, as well as the translocation of severalmolecular targets to the PSD of individual spines, but not to theirunstimulated neighbors (Bosch et al., 2014). Here, key postsynaptictargets include (a) signal transduction molecules such as CaMKII,(b) scaffolding proteins such as PSD95, Homer1b, Shank1b andSAP97, (c) neurotransmitter receptors such as GluA1-AMPARs, and(d) the F-actin depolymerization factor cofilin (Bosch et al., 2014).Interestingly, the spine enlargement is blocked by NMDAR antag-onists (Honkura et al., 2008).

Depending on the molecular processes induced by the stimulus,LTP can decay to the basal state within a few hours (called early LTP,or E-LTP) or can last for several hours/days (late LTP, or L-LTP). Theinitial AMPAR trafficking and cytoskeleton remodeling (spineenlargement) only involve changes in preexisting proteins. How-ever, the induction of an enduring L-LTP requires the synthesis ofnew proteins (Flexner et al., 1962; Parsons et al., 2006; Schafe andLeDoux, 2000). It involves both the local translation (Bradshawet al., 2003) and nuclear gene transcription (Bailey et al., 1999;Helmstetter et al., 2008).

In the last decade, it became clear that existing protein degra-dation is also required for LTP induction (Dong et al., 2008; Fonsecaet al., 2006) and memory consolidation (Jarome et al., 2011; Lopez-Salon et al., 2001). The protein degradation process initially in-volves the ubiquitination of certain proteins. Subsequently, theseproteins are delivered to the proteasome systemwhere they will bedegraded. Inhibitors of the ubiquitin-proteasome system enhanceE-LTP, but impair L-LTP (Dong et al., 2008). They also disruptmemory consolidation (Artinian et al., 2008).

The steps summarized above describe how memory is formed.However, how is it maintained over time? A memory can last awhole life. Theremust bemechanisms that keepmemory alivewiththe passage of time. Shortly after memory acquisition or LTP in-duction, an enzyme called PKMz is translated and transported intothe dendritic spine (Sacktor, 2011). PKMz has some peculiar fea-tures that make it an important candidate to be considered anessential player in the maintenance of memory: (a) it is an atypicalprotein kinase without the regulatory domain, being constantlyactive; (b) it controls its own synthesis, that is, it can be self-perpetuated; and (c) it controls GluA2-AMPAR stabilization in thePSD. It has been shown that a direct infusion of PKMz increases thenumber of AMPAR (Ling et al., 2002). On the other hand, theapplication of the z inhibitory peptide (ZIP) (PKMz inhibitor) issufficient to disrupt a fully consolidated memory as well as L-LTP(Migues et al., 2010; Pastalkova et al., 2006; Shema et al., 2007),suggesting that PKMz plays an important role in memorymaintenance.

Despite the fact that we are constantly making new memoriesthroughout our lives, the destiny of most of those memories is to beforgotten, or they will be modified in order to keep their relevanceover time. However, the mechanisms through which this happensremain obscure. In the following sections of this review, we willapproach how memories are forgotten, focusing on the recentstudies suggesting that it is an active process initiated by iGluRs.

3. Toward the neurobiology of forgetting: role of iGluRs inthe active decay of long-lasting memory traces

In 1986, Richard Morris and colleagues provided some of the

Please cite this article in press as: Sachser, R.M., et al., Forgetting of whglutamate receptors on memory formation, maintenance, andj.neuropharm.2016.07.015

first evidence showing that blocking hippocampal NMDARs withthe competitive antagonist AP5 impairs LTP induction as well asspatial LTM consolidation (Morris et al., 1986). In fact, over the pastthree decades, an increasing number of studies broadly support theclaim that NMDAR-dependent activation plays critical roles con-trolling learning and memory processing by modulating AMPARtrafficking (for comprehensive reviews, see Herring and Nicoll,2015; Huganir and Nicoll, 2013; Morris, 2013). However, theinvolvement of NMDARs on L-LTP decay was only uncovered in theearly 2000s (Villarreal et al., 2002). In this pioneering study, Vil-larreal and colleagues found that systemic chronic administrationof the NMDAR antagonist CPP, when started 48 h after LTP induc-tion in the dentate gyrus, blocks the natural decay of the L-LTP forseveral days in freely moving animals. Interestingly, the same doseof CPP used to block L-LTP decay also impairs LTP induction wheninjected 12 or 24 h before theta burst stimulation. Therefore, itappears that NMDARs are implicated in LTP induction and itsmaintenance through independent cellular mechanisms. Addi-tionally, in order to confirm these electrophysiological findings,daily injections of CPP sustains hippocampus-dependent spatialLTM that otherwise would be forgotten (Villarreal et al., 2002). Thiswas the first demonstration showing the requirement of NMDAR inregulating L-LTP decay and time-dependent forgetting of LTM. Afterthat, only two studies have been dedicated to replicate these dataso far (Sachser et al., 2016; Shinohara and Hata, 2014). As a matterof fact, these results reveal that blocking Ca2þ influx throughNMDAR, after a period in which LTP/LTM is stabilized, preventmemory forgetting.

We recently showed that daily systemic post-acquisition in-jections of memantine or MK-801 (two noncompetitive NMDARantagonists) prevent the natural decay of fully consolidated LTMs.For example, using the hippocampus-dependent object location(OL) task, while the control group starts to forget between 3 and 5days after learning, animals treated chronically with MK-801 stillexpressed a significant preference for the displaced object duringtest sessions conducted up to 10 days after training. Similar resultsin the same conditions were obtained using nimodipine (LVDCCblocker) or FK506, an inhibitor of the protein phosphatase calci-neurin (CaN) (Sachser et al., 2016). It seems that after memoryconsolidation, the resultant Ca2þ influx through both NMDARs andLVDCCs activate CaN-mediated signaling in order to induce time-dependent forgetting. Shinohara and Hata (2014) have found thatdaily infusions of the NMDAR antagonist D-AP5 directly into thehippocampus prevent memory decay in the Morris water mazetask. Concerning the possibility that different NMDAR subunitsmayplay different roles in regulating LTP decay, we have demonstratedthat depotentiation of CA1-evoked postsynaptic plasticity requiresthe activation of GluN2B-containing NMDARs (GluN2B-NMDAR)(Sachser et al., 2016), as proposed by Hardt et al. (2013).

GluA2-AMPAR trafficking has been recently implicated indetermining how long LTP and LTMwill persist with the passage oftime (Dong et al., 2015; Hardt et al., 2014b, 2013; Migues et al.,2016). In a well-designed study conducted by Migues et al.(2016), researchers found that forgetting of multiple types ofassociative LTMs requires the internalization of GluA2-AMPAR.Chronically blocking their synaptic removal using the peptideGluA23Y in either the hippocampus or in the infralimbic cortexsustain LTMs over time. Moreover, the application of GluA23Y pre-vents depotentiation of E-LTP (Migues et al., 2016) and L-LTP (Donget al., 2015). Similarly, blocking GluA2-AMPAR endocytosis alsorescue both LTP and LTM impairments in the APP23/PS45 mousemodel of Alzheimer's disease (Dong et al., 2015). Importantly,GluA23Y has no effects on basal synaptic transmission as well as inLTP induction (Dong et al., 2015). Collectively, these data stronglysuggest that the resultant postsynaptic Ca2þ influx through

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activation of GluN2B-NMDAR (or LVDCC) controls GluA2-AMPARendocytosis, revealing one of the main biological signaturesinvolved in forgetting in both physiological and pathologicalconditions.

Between this NMDAR-dependent activation and its downstreamprocesses that determine GluA2-AMPAR endocytosis duringforgetting, it is reasonable to think that several intracellularsignaling cascades sensitive to Ca2þ may be involved in LTP decay.Among these key targets, we highlight CaN, a Ca2þ-dependentserine/threonine phosphatase that is robustly implicated inlearning and memory. It has been demonstrated that CaN de-phosphorylate AMPARs during certain forms of postsynaptic plas-ticity, such as synaptic scaling (Kim and Ziff, 2014) and LTD(reviewed in Baumg€artel and Mansuy, 2012). Recently, it has beensuggested that CaN-mediated LTD requires internalization of CP-AMPAR (Sanderson et al., 2016), a candidate process underlyinghomeostatic plasticity (Henley and Wilkinson, 2016; Kim and Ziff,2014). However, the mechanisms in which CI-AMPAR regulateLTD or synaptic downscaling still remain obscure. Sanderson et al.(2016) reported that hippocampal CP-AMPARs undergo endocy-tosis when the complex formed by PKA and the scaffolding proteinAKAP150 is destabilized through CaN-mediated signaling(Sanderson et al., 2016). The same effect upon AMPAR destabili-zation was elegantly described by Tomita et al. (2005), whichdemonstrated that AMPARs removal during LTD is regulated byCaN-dependent dephosphorylation of stargazin. Stargazin isinvolved in AMPAR stabilization through their C-terminal in-teractions with the main scaffolding protein PSD95 (Tomita et al.,2005). Supporting these findings at the behavioral level, we andothers have demonstrated that CaN induces forgetting of spatialLTM (Genoux et al., 2002; Sachser et al., 2016), possibly by con-trolling AMPAR endocytosis through activation of protein phos-phatase 1 (PP1) (Genoux et al., 2002), or by directly destabilizingprotein-protein interactions such as stargazin-PSD95 (Tomita et al.,2005) and/or PKA-AKAP150 (Sanderson et al., 2016). Nevertheless,we cannot rule out the possibility that other important intracellularsignaling cascades mediated by CaN regulate forgetting throughAMPAR destabilization. For instance, CaN also modulates (a) LTPdepotentiation (Jouvenceau et al., 2003), (b) presynapticendocannabinoid-dependent inhibitory LTD (Castillo et al., 2012;Heifets et al., 2008), (c) group 1 metabotropic-dependent LTD(Lüscher and Huber, 2010), and (d) hippocampal NMDAR-dependent LTD that occurs through dephosphorylation ofPIP5Kɣ661 (phosphatidylinositol 4-phosphate 5-kinaseɣ661), themajor phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2)-producingenzyme in the brain (Unoki et al., 2012).

Another emergent model for the synaptic retention of GluA2-AMPAR in regulating memory persistence involves the activity ofPKMz (Hardt et al., 2010; Yao et al., 2008). This unique featurecomes from the unusual structure of the enzyme as a secondmessenger-independent, constitutively active isoform of PKC(Sacktor, 2012, 2011). The GluA2-AMPARs stabilization in the PSD isa necessary step for memory maintenance (Migues et al., 2010). Itrequires the persistent activation of PKMz, which enhances theGluA2-AMPAR interaction with the protein N-ethylmaleimide-sensitive factor (NSF) in order to keep these receptors stabilized atslots within the PSD (Lüscher et al., 1999; Nishimune et al., 1998;but reviewed in Sacktor, 2011, 2012). Indeed, intrahippocampalinfusions of pep2m and pepR845A, two interference peptides thathave been shown to disrupt the binding of NSF to C-terminal tail ofthe GluA2-AMPAR, impair the persistence of both OL as well ascontextual fear memory in rats (Migues et al., 2014), possibly byallowing the interaction of PICK1 (protein interacting with C kinase1) with the GluA2-AMPAR. In fact, it has been postulated thatactivated PICK1, as well as the brefeldin resistant Arf-GEF 2 (BRAG2,

Please cite this article in press as: Sachser, R.M., et al., Forgetting of whglutamate receptors on memory formation, maintenance, andj.neuropharm.2016.07.015

a guanine-exchange factor activated by GTPase proteins), areinvolved in the synaptic removal of GluA2-AMPAR. For an overviewof these mechanisms, see Sacktor (2011, 2012). Previous studieshave shown that inhibiting PKMz with ZIP disrupts L-LTP by trig-gering GluA2-AMPAR endocytosis (Yao et al., 2008), which in turnalso abolishes the maintenance of LTMs (Hardt et al., 2010; Migueset al., 2010). Interestingly, Dong et al. (2015) demonstrated that ZIP-induced hippocampal L-LTP decay was rescued by GluA23Y. Takentogether, these and other important studies have indicated thatPKMz, by modulating NSF-GluA2 interaction at postsynaptic sites,regulates LTM persistence. However, it has been shown that PKMzis not involved in hippocampus-dependent synaptic plasticity un-derlying learning and memory (Lee et al., 2013; Volk et al., 2013). Itis possible that other isoforms of PKM may compensate LTPmaintenance when PKMz is knocked out, such as PKCiota (Sacktor,2012). Indeed, both enzymes are inhibited by ZIP. Thus, forgettingmight be caused by PKMz degradation, thereby controlling GluA2endocytosis in a mechanism that isdat least partiallydsensitive toCa2þ (Hardt et al., 2013, 2014a,b).

It is well established that the amount of postsynaptic surfaceexpression of GluA2-AMPAR in the PSD correlates with memoryperformance (Migues et al., 2010). In accordance, recent studiesdemonstrated that forgetting relies on GluA2-dependent synapticremoval (Dong et al., 2015; Hardt et al., 2013; Migues et al., 2016,2010). On the other hand, to support memory expression with thepassage of time, GluA2-AMPAR must be stabilized within the PSDby recruiting structural elements that play crucial roles in L-LTPmaintenance. In fact, NMDAR-dependent LTP- and LTD rely onspecific changes in F-actin remodeling at dendrites. LTP requirespine enlargement, whereas LTD is mediated by spine shrinkage(Anggono and Huganir, 2012; Bosch and Hayashi, 2012; Cingolaniand Goda, 2008; Fortin et al., 2012; Herring and Nicoll, 2016). Thestability of spine enlargement seems to play a critical role insustaining L-LTP in a nondecaying state over time. For example,Fukazawa et al. (2003) found that these effects on L-LTP mainte-nance require inactivation of cofilin in a NMDAR-dependentmanner, suggesting that L-LTP is maintained when F-actin depo-lymerization factors are inhibited. Thus, NMDAR-dependent F-actin remodeling may also participate in processes mediatingforgetting. Supporting this view at the behavioral level, unpub-lished results from our group indicate that hippocampus-dependent LIMK-cofilin pathway regulates contextual fear mem-ory consolidation, since immediately posttraining intra-hippocampal infusions of LIMKi 3 (LIMK inhibitor, which in turnactivates the actin depolymerization factor, cofilin) causes retro-grade amnesia during the test session conducted 48 h afterlearning. Thus, by regulating spine shrinkage through F-actindepolymerization, we suggest that LIMK-cofilin pathway, regu-lated by both Rac1-PAK- and RhoA-ROCK-mediated signalingcascades, provides the physical substrate involved in certain formsof LTP decay such as depotentiation, synaptic downscaling andLTD-mediated mechanisms.

In this scenario, besides the roles that LVDCCs and GluN2B-NMDARs play on forgetting (Sachser et al., 2016), we cannot ruleout that many other intracellular Ca2þ sources such as the endo-plasmatic reticulum may also participate in processes determiningthe fate of LTP/LTM. Overall, the vast majority of the studies pub-lished so far have indicated that Ca2þ-dependent signaling throughactivation of NMDARs plays critical roles governing functional aswell structural synaptic plasticity by controlling (a) GluA2-AMPARtrafficking and (b) dendritic spine remodeling. Thus, taking intoaccount that L-LTP maintenance and LTM persistence requiresmultiple postsynaptic stabilization-dependent mechanisms in or-der to endure, destabilizing these protein-protein interactionsinvolved in anchoring GluA2-AMPAR may represent the biological

at was once learned: Exploring the role of postsynaptic ionotropicdecay, Neuropharmacology (2016), http://dx.doi.org/10.1016/

R.M. Sachser et al. / Neuropharmacology xxx (2016) 1e10 5

nature underpinning memory loss. In the following section, wewillfurther discuss important results regarding the involvement ofiGluRs controlling different intracellular signaling cascadesengaged in GluA2-AMPARs destabilization.

4. How retrieval affects the fate of long-lasting memorytraces?

Following initial encoding, memory is in an unstable state andrequires the engagement of specific mechanisms in order to bestored as a LTM. In fact, there is a continuous balance betweenopposing active processes that determine if memory will bemaintained or forgotten. If forgetting does not take place, memoryis maintained in a long lasting manner allowing its retrieval.However, retrieval is not a simple passive readout of stored infor-mation. It can greatly affect memory stability, leading to itsstrengthening, weakening or reinterpretation.

Following retrieval, memory may undergo a transformationfrom a stable to an unstable state, and it must be restabilized by thereconsolidation process in order to persist (Nader and Einarsson,2010). If reconsolidation fails to take place, memory fades andamnesia occurs (Nader et al., 2000). This implies that even a robustmemory that is being actively supported by maintenance mecha-nisms may decay when it is recalled. At first glance, the existence ofa process that can re-determine memory fate every time it isrecalled may appear to be counterintuitive. Given the constanteffort to maintain a memory trace, why would retrieval inducememory instability? It happens that it grants memory withmalleability, which plays a key role in maintaining its adaptiverelevance (Lee, 2009). For instance, it allows memory change bystrengthening its original associations (Forcato et al., 2011;Fukushima et al., 2014; Lee, 2008). Also it can be updated withnew information, whichmay lead to theweakening the original CS-US association (Monfils et al., 2009; Schiller et al., 2013; Haubrich etal., 2015) or change its content (De Oliveira Alvares et al., 2013; Lee,2010; Sierra et al., 2013). Thus, the destabilization-reconsolidationprocess makes memory dynamic and prone to changes. Interest-ingly, the mechanisms underlying memory destabilization andreconsolidation following retrieval are strikingly similar to those offorgetting and maintenance.

A critical step for triggering memory destabilization andreconsolidation is the activation of GluN2B-NMDAR, which hasbeen shown to promote (a) LTD and protein degradation(Hardingham et al., 2002) and (b) mediates forgetting (Sachseret al., 2016). For instance, the selective GluN2B-NMDAR antago-nist ifenprodil prevents the amnestic effect of reconsolidationdisruptive interferences (Crestani et al., 2015a; Ben Mamou et al.,2006; Milton et al., 2013; De Oliveira Alvares et al., 2013) andreconsolidation-mediated fear memory updating (Haubrich et al.,2015) when administered before retrieval. As discussed before,ifenprodil also blocks depotentiation after the stabilization of CA1-evoked postsynaptic plasticity in vivo (Sachser et al., 2016). It in-dicates that GluN2B-NMDARs are critical for triggering memorydestabilization and, if blocked, memory remains stable. Takentogether, it appears that blocking Ca2þ through GluN2B-NMDARmay prevent memory destabilization as well as forgetting-dependent mechanisms. In agreement with this view, it has beenshown that very strong memories are resistant to be destabilizeddue to a downregulation of GluN2B-NMDAR (Wang et al., 2009).Importantly, ifenprodil has no effect when administered aftermemory reactivation (BenMamou et al., 2006), therefore the role ofGluN2B-NMDAR is limited to initiating the destabilization phasebut not to reconsolidation.

Following retrieval and GluN2B-NMDAR activation, there is arapid decrease of CI-AMPARs that is matched by an increase of CP-

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AMPARs (Clem and Huganir, 2010; Hong et al., 2013; Rao-Ruiz et al.,2011). Importantly, because they are less stable at synapses, CP-AMPARs are involved in the LTD induction, which indicates thatthe transient labile state of memory following retrieval is a result ofsuch AMPAR trafficking (Clem and Huganir, 2010). In accordance,blocking GluA2-AMPAR endocytosis prevent the effects of recon-solidation disruptive agents (Hong et al., 2013) andreconsolidation-mediated updating (Rao-Ruiz et al., 2011). GluA2-AMPAR endocytosis is also critical for forgetting (Dong et al.,2015; Migues et al., 2016, 2010), which further highlights thesimilarity between the natural decay of LTM and retrieval-drivendestabilization. In the next hours after the initial destabilization,however, there is a gradual increase in CI-AMPARs expression(Clem and Huganir, 2010; Hong et al., 2013; Rao-Ruiz et al., 2011).This correlates with the reconsolidation phase that is believed toreturn memory to a stable state. Although GluN2B-NMDARs arecritical for destabilization but not reconsolidation, NMDAR are alsoimportant for the reconsolidation phase given that non-selectiveNMDAR antagonist leads to amnesia when administered duringreactivation (Brown et al., 2008; Lee and Everitt, 2008;Przybyslawski and Sara, 1997; Winters et al., 2009). Milton et al.(2013) have shown that reconsolidation, but not destabilizationthat precedes it, is mediated not by GluN2B but instead throughGluN2A-containing NMDARs (GluN2A-NMDAR). In fact, GluN2A-NMDARs are associated with LTP and increased CREB phosphory-lation, two processes associated with the reconsolidation phase(Clarke et al., 2010; Hall et al., 2001; Maddox et al., 2014).

Hence, retrieval renders memory unstable following memoryreactivation through both NMDAR- and AMPAR-mediated mecha-nisms that closely mirror those involved in memory forgetting.Other evidence supports the close similarities between memorydestabilization and forgetting. For instance, LVDCC activation isinvolved in both memory destabilization (Cassini et al., 2013;Crestani et al., 2015b; De Oliveira Alvares et al., 2013; Haubrichet al., 2015; Sierra et al., 2013; Suzuki et al., 2009) and forgetting(Sachser et al., 2016). Moreover, CaN activity is also involved in bothprocesses (Fukushima et al., 2014; Sachser et al., 2016). In light ofthe findings obtained by Fukushima and colleagues, it appears thatbothmemory updating and forgetting-dependent mechanisms willlikely rely on CaN-induced proteasome-dependent protein degra-dation (Fukushima et al., 2014). As a matter a fact, we believe thatthe ubiquitin-proteasome system plays critical roles underdestabilization-dependent mechanisms involved in memoryupdating/forgetting.

5. Ubiquitin-proteasome system may regulate long-memorymaintenance

Considered an important element of synaptic function, partic-ularly at the level of dendritic spines, it is widely accepted that theactivity of local ubiquitin proteasome system (UPS) is involvedduring formation and maintenance of LTM. Here we highlight thatthe UPS may be involved in controlling the destabilization-dependent mechanisms discussed so far. Thus, the postsynapticmalleability necessary to induce destabilization of a stable mem-ory trace (for example, via Ca2þ influx through GluN2B-NMDARactivation) may also be considered in regulating memoryforgetting.

The UPS is a complex network of different ubiquitin ligases andinterconnected protein structures involved in the regulation ofprotein degradation in neurons (Bingol and Sheng, 2011; Mabb andEhlers, 2010; Patrick, 2006). Briefly, the proteins become reversiblytargeted for degradation through a series of steps in which thesmall protein modifier ubiquitin (76 amino-acid) is covalentlybound to a target substrate (Hershko and Ciechanover, 1998). These

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steps are catalyzed by the sequential action of three enzymes: theubiquitin-activating enzyme (E1), the ubiquitin-conjugatingenzyme (E2), and the ubiquitin ligase (E3) (Hicke and Dunn,2003). The E3 ligase transfers ubiquitin to its target at lysine resi-dues (Pickart, 2001). The substrate can acquire different ubiquitinarrangements, from monoubiquitin to polyubiquitin chains, linkedtogether at specific lysine residues (Haglund et al., 2003). Appar-ently, longer polyubiquitin chains and lysine-48 linkage provide themaximal signal for degradation (Fioravante and Byrne, 2011) whilelysine-63 linkage often targets substrates for other non-proteolyticfunctions (Rieser et al., 2013).

Concerning post-translational regulation of AMPAR traffickingunder synaptic activity, several studies have shown that differentAMPAR subunits are ubiquitinated in mammalian central neurons(Fu et al., 2011; Lin et al., 2011; Lussier et al., 2011; Patrick et al.,2003; Schwarz et al., 2010). For instance, it was identified thatGluA1-dependent ubiquitination is promoted by the E3 ligasecalled neural precursor cell expressed developmentally down-regulated (Nedd4) (Camera et al., 2016; Lin et al., 2011; Schwarzet al., 2010), as well as by the ubiquitin E3 ligase namedanaphase-promoting complex (APC), which is specifically reportedto control downregulation of synaptic GluA1 induced by ephrinreceptor 4 (EphA4). EphA4 is indeed involved with the retraction ofdendritic spines (Fu et al., 2011, 2007; Murai et al., 2003), which asmentioned before, is considered one of the main features under-pinning LTD-like mechanisms. Interestingly, most of these studieswere not able to find any GluA2-AMPAR ubiquitination, arguingthat this mechanism is specific for GluA1-AMPARs. However,Lussier et al. (2012) have demonstrated that inactivating E3 ligase(by expressing a dominant negative or a specific shRNA) increases

Fig. 1. (A) After memory consolidation, forgetting may be initiated by Ca2þ influx through Gthe main targets is CaN. This phosphatase may induce dephosphorylation of stargazin, anprotein PSD95. According to our model, the end of these dephosphorylation processes leadAMPAR). CaN may also promote the dephosphorylation of PP5Kg661. Dephosphorylated PP5local production of PI(4,5)P2 to induce AMPAR endocytosis. Another proposed mechanismthrough the interaction with N-ethylmaleimide-sensitive factor (NSF) The resultant postsyAMPARs at slots within the PSD. Ca2þ-dependent signaling through GluN2B-NMDAR maspines. In this case, Ca2þ signals CaMKIIb to activate both Rac1-PAK-LIMK and RhoA-ROCphosphorylated cofilin. Cofilin destabilizes preexisting F-actin, which induces LTD-like mechLTP decay is BRAG2, which also participates in GluA2-AMPAR synaptic removal. (B) Schem

Please cite this article in press as: Sachser, R.M., et al., Forgetting of whglutamate receptors on memory formation, maintenance, andj.neuropharm.2016.07.015

surface AMPAR expression in culture neurons, being involved inboth activity-dependent ubiquitination of GluA1 and GluA2(Lussier et al., 2015, 2012). In addition, a more recent paperrevealed that all AMPAR subunits (GluA1-4) undergo post-translational ubiquitination in an activity and Ca2þ-dependentmanner (Widagdo et al., 2015). In this study, by mapping the mainC-terminal lysine ubiquitination sites on GluA1 and GluA2, theauthors have elegantly suggested an important role for ubiquiti-nation in the regulation of post-endocytic sorting and degradationof AMPARs (Widagdo et al., 2015). Besides this evidence on AMPARubiquitination, other important studies contributed to the viewthat UPS may be involved in destabilization-dependent mecha-nisms. For example, multiple PSD scaffolding proteins undergoubiquitination, such as PSD95 (Colledge et al., 2003), Shank, GKAP/SAPAP and AKAP79/150 (Ehlers, 2003; Hung et al., 2010), suggest-ing an ubiquitin-dependent regulation of postsynaptic assemblyand stability. This hypothesis on the involvement of the UPS in L-LTP/LTM maintenance in the behavioral level, however, remainsobscure and certainly needs more attention in the field.

In contrast with the effect of ubiquitination on AMPAR synapticdegradation (Schwarz et al., 2010), ubiquitin can be recycled andremoved from ubiquitin-conjugated proteins by a large family ofdeubiquitinating enzymes (DUBs) (Millard and Wood, 2006;Nijman et al., 2005; Reyes-Turcu et al., 2009; Soboleva and Baker,2004). Hence, DUBs provide important negative regulation ofprotein degradation. Recently, Huo et al. (2015) reported that theDUB called USP46 could act as a specific deubiquitinating enzymefor both GluA1 and GluA2-containing AMPARs. For instance, thisgroup has demonstrated in vitro that suppressing ubiquitination byUSP46 overexpression slows down the degradation and prolongs

luN2B-NMDAR that activates several molecular targets in postsynaptic neurons. One ofauxiliary transmembrane AMPAR protein, which is connected to the main scaffoldings to the synaptic removal of GluA2-containing Ca2þ impermeable AMPAR (GluA2-CI-

Kg661 interacts with the clathrin-mediated complex by recruiting AP-2, resulting in thefor controlling forgetting involves PKMz. PKMz maintains postsynaptic GluA2-AMPARnaptic Ca2þ influx might lead to PKMz downregulation that normally stabilize GluA2-y also regulate memory decay through structural changes at the level of dendriticK-LIMK pathways. It promotes F-actin depolymerization by controlling the levels ofanisms such as spine shrinkage. Another possible target involved in Ca2þ-dependent L-atic illustration of the reviewed data.

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R.M. Sachser et al. / Neuropharmacology xxx (2016) 1e10 7

the half-life of AMPAR (Huo et al., 2015). The behavioral output ofthis manipulation, however, is still an open question.

It is well-established that the UPS is tightly regulated in all cellsto control the ubiquitination and degradation of target proteinswith remarkable spatial and temporal precision. In fact, protea-somes are recruited to spines following NMDAR activation (Bingoland Schuman, 2006). In particular, it has been proposed thatCaMKII induces the proteasome activity by phosphorylation of theRpt6 proteasome subunit as well as its recruitment to the dendriticspines (Bingol and Sheng, 2011; Djakovic et al., 2012).

It has been shown that inhibiting protein degradation in distinctbrain structures such as the amygdala and the dorsal hippocampus,in different memory tasks such as Morris water maze, inhibitoryavoidance and fear conditioning, impairs memory consolidation(Artinian et al., 2008; Jarome et al., 2011; Lopez-Salon et al., 2001).Interestingly, inhibiting the UPS prevents the reconsolidationimpairment caused by the protein synthesis inhibitor anisomycin(Jarome et al., 2011; Lee, 2008). Thus, it strongly supports the ideathat protein degradation is required for memory updating throughdestabilization-mediated mechanisms (Lee and Everitt, 2008; Lee,2008). Indeed, the hypothesis that protein degradation accom-panies changes in protein synthesis during LTM formation recentlyhas started to gain attention (Fioravante and Byrne, 2011; Jaromeand Helmstetter, 2014; Jarome et al., 2011).

In conclusion, based on the findings suggesting that memorymaintenance relies on AMPAR trafficking in the PSD (Dong et al.,2015; Hardt et al., 2014a,b; Migues et al., 2010), the mechanismscontrolling AMPAR turnover through both protein synthesis anddegradation may be essential in different decay-like processes,such as synaptic depotentiation underpinning memory decay. Webelieve that the degradation of GluA2-CI-AMPARs as well as PSDscaffolding proteins are essential to determine the memory fate,because (a) it can be rebuilt in a strengthened form, (b) modifiedwith its content updated or (c) tagged to be forgotten.

6. Concluding remarks and future directions

Understanding the cellular and molecular basis underlyingforgetting may shed new light on the development of targeted in-terventions that might ultimately be clinically useful. Based onexperimental findings obtained in rodents, we suggest that theCa2þ-dependent signaling through GluN2B-NMDAR activation fol-lowed by GluA2-AMPAR endocytosis plays a critical role in regu-lating memory destabilization and forgetting. Our molecular modelattempting to explain how L-LTP/LTM decay is illustrated in Fig. 1.Thus, we believe that understanding the neurobiology of forgettingmay provide new behavioral and pharmacological strategies aimedto prevent age-induced memory impairment, or to further accel-erate forgetting of traumatic, maladaptive long-term memoriessuch as those classically observed in psychiatric conditions such asposttraumatic stress disorder (PTSD) and drug addiction.

Conflict of interest

The authors declare no competing financial interests related tothe subject matter of this work.

Acknowledgements

We thank Fernanda Lotz for her careful review.

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