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Neuropharmacology 64 (2013) 13e26

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Neuropharmacology

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

Invited review

The NMDA receptor as a target for cognitive enhancement

Graham L. Collingridge a,b,*, Arturas Volianskis a, Neil Bannister a, Grace France a, Lydia Hanna a,Marion Mercier a, Patrick Tidball a, Guangyu Fang a, Mark W. Irvine a, Blaise M. Costa c,Daniel T. Monaghan c, Zuner A. Bortolotto a, Elek Molnár a, David Lodge a, David E. Jane a

aMRC Centre for Synaptic Plasticity, School of Physiology and Pharmacology, University of Bristol, Bristol BS1 3NY, UKbDepartment of Brain and Cognitive Sciences, Seoul National University, Seoul, Republic of KoreacDepartment of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE 68198-6260, USA

a r t i c l e i n f o

Article history:Received 15 May 2012Received in revised form22 June 2012Accepted 24 June 2012

Keywords:Synaptic plasticityNMDA receptorCognitive enhancementLTPSynaptic transmissionHippocampusPositive allosteric modulators

Abbreviations: AChR, acetylcholine receptor; AKAproteins; AMPAR, AMPA receptor; CaMKII, Ca2þ/cakinase; CK2, casein kinase II; D1R, dopamine 1 recsynaptic current; EPSP, excitatory postsynaptic potepostsynaptic potentials; GABAAR, GABAA receptor; GAG-protein-coupled receptors; iGluR, ionotropic glutampostsynaptic potential; LTP, long-term potentiation;choline receptor; mGluR, metabotropic glutamatereceptor; NMDAR-LTP, NMDA receptor dependent lonpituitary adenylate cyclase activated peptide 1 receptoprotein kinase C; PSD95, postsynaptic density proteityrosine phosphatase.* Corresponding author. MRC Centre for Synaptic P

and Pharmacology, University of Bristol, Bristol BS1 311913.

E-mail address: [email protected] (G.L

0028-3908/$ e see front matter � 2012 Elsevier Ltd.http://dx.doi.org/10.1016/j.neuropharm.2012.06.051

a b s t r a c t

NMDA receptors (NMDARs) play an important role in neural plasticity including long-term potentiationand long-term depression, which are likely to explain their importance for learning and memory.Cognitive decline is a major problem facing an ageing human population, so much so that its reversal hasbecome an important goal for scientific research and pharmaceutical development. Enhancement ofNMDAR function is a core strategy toward this goal. In this review we indicate some of the major ways ofpotentiating NMDAR function by both direct and indirect modulation. There is good evidence that bothpositive and negative modulation can enhance function suggesting that a subtle approach correctingimbalances in particular clinical situations will be required. Excessive activation and the resultantdeleterious effects will need to be carefully avoided. Finally we describe some novel positive allostericmodulators of NMDARs, with some subunit selectivity, and show initial evidence of their ability to affectNMDAR mediated events.

This article is part of a Special Issue entitled ‘Cognitive Enhancers’.� 2012 Elsevier Ltd. All rights reserved.

1. Introduction

The NMDA receptor (NMDAR) is a prime target for cognitiveenhancement since it is centrally involved in cognitive processes.Approximately 30 years ago, it was shown that the transient acti-vation of NMDARs is the trigger for the induction of long-termpotentiation (LTP) at synapses made between CA3 and CA1

P79/150, A-kinase anchoringlmodulin-dependent proteineptor; EPSC, excitatory post-ntial; fEPSP, field excitatoryBABR, GABAB receptor; GPCR,ate receptor; IPSP, inhibitorymAChR, muscarinic acetyl-receptor; NMDAR, NMDA

g-term potentiation; PAC1R,r; PKA, protein kinase A; PKC,n 95; STEP, striatal-enriched

lasticity, School of PhysiologyNY, UK. Tel.: þ44 (0) 117 33

. Collingridge).

All rights reserved.

pyramidal neurons in the hippocampus (Collingridge et al., 1983).Shortly afterwards direct evidence was provided that NMDARs arealso required for forms of hippocampus dependent learning andmemory (Morris et al., 1986). These findings have led to numerousstudies into the role of NMDARs in synaptic plasticity, learning andmemory and have placed the NMDAR at the heart of cognition. SinceNMDARs are required for these processes the simple notion is thatboosting NMDAR function should enhance cognition and, indeed,there is evidence that this may be true under certain circumstances(Tang et al., 1999). We will commence our discussion on thisassumption: that NMDAR activation leads to LTP and that thisequates with learning and memory and consequently enhancingNMDAR function is good for cognition. This is, of course, a gross over-simplification. Most importantly, NMDAR activation can result inpathological conditions, such as epilepsy (Croucher et al., 1982),neuronal cell death (Simon et al., 1984) and hyperalgesia (Davies andLodge, 1987). Therefore, too much activation of the NMDAR isdetrimental. The key is to boost the physiological function withoutpromoting the tendency for pathological consequences.

NMDARs are obligate heterotetramers formed from assembliesof GluN1 subunits with GluN2A-D and GluN3A/B. In addition,GluN3A can assemble with GluN1 (without other GluN2 subunits)to form excitatory, Ca2þ-impermeant glycine receptors. Eight

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G.L. Collingridge et al. / Neuropharmacology 64 (2013) 13e2614

possible variations of the GluN1 subunit arise by alternativesplicing of a single gene transcript. The presence of one splicecassette at the N-terminal region of GluN1 and two independentconsecutive splice variants at the C terminus have been identified.Therefore, a large number of different NMDARs with differingfunctional and pharmacological properties exist in different parts ofthe brain or at different stages in development (Molnár, 2008).Unusually for the ionotropic glutamate receptors (iGluRs), L-gluta-mate is not the only agonist for the NMDAR. Glycine and D-serine,two neutral endogenous amino acids, are co-agonists and thepresence of one or other along with glutamate are needed for thereceptor to function. The binding sites for glutamate and glycine/D-serine are found on different subunits e glycine binds to the GluN1(and GluN3) subunits while glutamate binds to the GluN2 subunits.Consequently, both subunit types are required to generate a fullyfunctioning NMDAR.

The NMDAR has several unique properties that are important forits function. Foremost, it is sensitive to block by low micromolarconcentrations of magnesium ions (Mg2þ) (Ault et al., 1980) ina manner that is highly voltage-dependent (Nowak et al., 1984;Mayer et al., 1984). The consequence of this block is such that atnormal resting membrane potentials (typically between �50and �75 mV) the NMDAR is largely blocked by Mg2þ from thesynaptic cleft. Depolarization greatly reduces the Mg2þ block sothat the participation of NMDARs in the synaptic response becomessubstantially greater (Collingridge et al., 1988). This propertyexplains the “Hebbian” nature of synaptic plasticity, whereby theNMDAR senses the co-incidence between presynaptic activity(which releases L-glutamate to bind to the NMDAR) and post-synaptic activity (defined as enough depolarization to reduce theMg2þ block sufficiently to trigger the induction of plasticity). Weshall refer to this depolarization as “Hebbian depolarization”. TheNMDAR is also directly permeable to Ca2þ and this is extremelyrelevant for both its physiological and pathological actions.

Due to the complex molecular organization, functional andpharmacological properties of NMDARs, the design of agents toboost cognition via the regulation of NMDAR function needs to takeaccount of many factors. In the present article, we discuss ways inwhich NMDAR function can be regulated. Broadly speaking,compounds that regulate NMDAR function do so in one of twoways. First, theymay interact with other proteins that then regulateNMDAR function indirectly. Second, they may bind directly to theNMDAR to regulate its function. In the present article we discusssome of the ways in which NMDAR function may be regulated anddescribe some recently reported NMDAR positive allostericmodulators (PAMs).

2. Indirect modulation

The properties of the NMDAR enables many forms of indirectmodulation, many of which are probably utilized physiologically forcognitive purposes and can be exploited, in principle, for the designof cognitive enhancing compounds. Some of the more importantindirect modulators are described below and illustrated schemat-ically in Fig. 1.

2.1. AMPARs

During the induction of LTP, Hebbian depolarization is providedin part by the temporal summation of AMPAR-mediated EPSPs(Collingridge, 1985). Therefore one way, in theory, of boostingNMDAR function is to enhance the depolarization provided by thesynaptic activation of AMPARs. This is one of the ideas behind theuse of positive allosteric modulators of AMPARs (AMPAR PAMs),compounds that bind to the AMPAR itself to enhance its function.

Following the initial descriptions of aniracetam (Ito et al., 1990),diazoxides and thiazides (Yamada and Rothman, 1992), includingcyclothiazide (Palmer and Lodge, 1993; Patneau et al., 1993) andbenzamides (Arai et al., 1994), AMPAR potentiators were found tolimit receptor desensitization and slow deactivation (Partin et al.,1996). Such AMPAR PAMs were shown to potentiate LTP presum-ably by indirect enhancement of NMDARs (Stäubli et al., 1994b), asdemonstrated in vivo (Vandergriff et al., 2001). In parallel withthese electrophysiological studies, AMPAR PAMs were soon shownto enhance learning and memory (Staubli et al., 1994a). Since then,many other structural classes have been described (Ward andHarries, 2010; Pirotte et al., 2010) and their positive effects oncognition in laboratory animals and human patients have beenextensively reported and reviewed (Morrow et al., 2006; Arai andKessler, 2007; O’Neill and Dix, 2007; Cleva et al., 2010; Lynchet al., 2011). The potential site of action of AMPAR PAMs, togetherwith other cognitive enhancing agents that may act at the gluta-matergic synapse, is shown schematically in Fig. 2.

2.2. GABARs

GABA receptors (GABARs) provide a powerful physiologicalregulation of NMDARs. During low frequency transmission thesynaptic activation of GABARs prevents NMDARs from contributingappreciably to the synaptic response by hyperpolarizing the neuronand thereby intensifying the Mg2þ block (Herron et al., 1985;Dingledine et al., 1986). GABAARs are activated rapidly whereasGABABRs are activated after a delay of around 20 ms but providea longer lasting hyperpolarization (Davies et al., 1990). Together,these two inhibitory synaptic responses effectively limit thesynaptic activation of NMDARs throughout its time-course.Consequently, blocking either GABAA or GABAB receptors maylead to the enhanced synaptic activation of NMDARs (Davies andCollingridge, 1996). Since the GABAAR mediated inhibitory post-synaptic potential (IPSP) coincides with the peak NMDAR synapticconductance, this is likely to have the most dramatic effect. Duringlow frequency synaptic transmission, a GABAAR antagonist enablesa noticeable activation of NMDARs (Herron et al., 1985; Dingledineet al., 1986) and the effect is magnified during high frequencytransmission, since it facilitates the temporal summation ofNMDAR-EPSPs to generate a larger Hebbian depolarization. Thiseffect can be sufficient to enhance the induction of LTP (Abrahamet al., 1986).

GABABRs provide a more complex regulation of NMDARs. Thepostsynaptic GABABR IPSPs helps limit the synaptic activation ofNMDARs and so its selective blockade is able to enhance theinduction of LTP (Olpe et al., 1993). However, GABABRs are alsolocated presynaptically where they function as both autoreceptors,inhibiting GABA release (Davies et al., 1990), and heteroreceptors,inhibiting glutamate release (Davies et al., 1993; Isaacson et al.,1993). The autoreceptor function is important for the induction ofLTP by theta/priming patterns of activity (Davies et al., 1991), whichare a more physiologically relevant pattern of activation thana conventional tetanus (Larson et al., 1986; Diamond et al., 1988).This is because theta frequencies are optimally tuned for thesuppression of GABAR-mediated IPSPs, via the autoreceptormechanism, and this promotes the synaptic activation of NMDARsby facilitating the Hebbian depolarization (Davies and Collingridge,1993). Antagonism of GABABR autoreceptors therefore inhibits theinduction of LTP when theta patterns of activity are used, bylimiting the synaptic activation of NMDARs. However, when longertrains are used to induce LTP (i.e, a tetanus) GABABRs are no longerrequired to suppress GABAR-IPSPs and so GABABR antagonists nolonger inhibit the induction of LTP. Whether the regulation ofGABABRs can be exploited to enhance cognition is not known. The

Fig. 1. Indirect modulation of NMDARs. (A) Schematic representation of some ways in which NMDAR function can be regulated indirectly. Neurotransmitters, and other neuronalregulators, can facilitate NMDAR function by augmenting the “Hebbian depolarization” and by intracellular regulation. NMDARs are important for (B) synaptic transmission (C) theinduction of LTP and (D) the induction of LTD. Note that NMDARs contribute considerably to the synaptic response during high frequency synaptic transmission; in this example theNMDAR-EPSP has summated with the AMPAR-EPSPs (shaded yellow) to fire several action potentials (adapted from Herron et al., 1986). LTP is induced by a brief period of highfrequency stimulation whilst LTD is induced by a prolonged period of low frequency stimulation. Key: Different types of receptor populations are shown by a colour-coded symbol.Inward current via AMPARs and NMDARs (carried mainly by Naþ) contributes to the Hebbian depolarization and is shown by a red arrow. Outward current (carried mainly by themovement of Kþ (GABAB) out of the cell or Cl� (GABAA) into the cell) opposes the Hebbian depolarization and is depicted by a blue arrow. Ca2þ entry is shown by the grey arrow andMg2þ by a black circle.

G.L. Collingridge et al. / Neuropharmacology 64 (2013) 13e26 15

prediction from these LTP experiments is that the selective antag-onism of postsynaptic GABABRs might have the desired effect. Thismight be possible since a greater occupancy of postsynapticGABABRs is required to elicit a response and so this response is themore sensitive to antagonism (Seabrook et al., 1990).

2.3. Acetylcholine receptors

The crucial role of acetylcholine in cognition has long beenrecognized (Sarter and Parikh, 2005). There is good evidence thatsome of its actions might be mediated via the regulation ofNMDARs. In particular, the stimulation of muscarinic AChRs(mAChRs) is known to facilitate the activation of NMDARs(Markram and Segal, 1990). This probably occurs via multiplemechanisms. Activation of mAChRs leads to depolarization ofneurons and so would be expected to facilitate the Hebbian depo-larization. Since mAChRs depolarize neurons via the inhibition ofKþ channels, the associated increase in membrane resistance willalso facilitate the Hebbian depolarization. A particularly interestingregulation is via the inhibition of SK channels that are located atsynapses and activated by Ca2þ entry during the synaptic activationof NMDARs (Buchanan et al., 2010). In addition, it is likely that theactivation of mAChRs facilitates the activation of NMDARs viamechanisms independent of Kþ channels. Low concentrations of

a mAChR agonist, carbachol, below those that appreciably affect Kþ

channels, can exert a powerful regulation of NMDARs, viaa pathway that has not been fully delineated but seems to beindependent of PKC and the release of Ca2þ from stores (Harveyet al., 1993). Activation of mAChRs can also lead to a long-lastingdepression of NMDAR mediated synaptic transmission, via theinduction of a form of synaptic plasticity. This effect is due to theinternalization of NMDARs and is triggered by IP3 receptor-mediated Ca2þ release from stores (Jo et al., 2010). Clearly, themAChR regulation of NMDARs is multifaceted and the direction ofthe regulation (enhancement or depression) depends on a varietyof factors.

2.4. Metabotropic glutamate receptors

Group I mGluRs (mGlu1 and mGlu5), which like muscarinic M1receptors couple to Gq11, are also able to regulate the activation ofNMDARs inmultipleways. For example, it was found that activationof group I mGluRs, using 3,5-dihydroxyphenylglycine (DHPG)(Fitzjohn et al., 1996), or more specifically mGlu5 receptors, using2-chloro-5-hydroxyphenylglycine (CHPG) (Doherty et al., 1997,Fig. 2), is able to directly potentiate the depolarization of CA1neurons induced by NMDA. This effect is very robust and has beenexploited in attempts to boost NMDAR function, though again its

Fig. 2. Potential sites of action of cognitive enhancers at glutamatergic synapses and structures of some compounds that potentiate NMDAR function. The key is the same as in Fig. 1.


mechanism has not been fully elucidated. The mGlu5 receptor andNMDARs can work in concert for induction of LTP (Bortolotto et al.,2005; Lanté et al., 2006) with mGlu5 playing an increasing rolewith age (Lanté et al., 2006). An mGlu5 receptor antagonist blockedLTP in the dentate gyrus and reduced performance on a radial mazetask (Manahan-Vaughan and Braunewell, 2005). A series of positiveallosteric modulators (PAMs) of mGlu5 receptors have beendeveloped and shown to facilitate the activation of NMDARs (seeVinson and Conn, 2012 for a review) and enhance LTP (Ayala et al.,2009; Kroker et al., 2011). These compounds have been found toincrease behavioural flexibility in a set-shifting paradigm (Darrahet al., 2008), to enhance novel object recognition and to reduceimpulsivity in a five choice serial reaction time test (Liu et al., 2008),to reverse cognitive deficits induced by MK-801 (Vales et al., 2010)and to improve learning deficits in the methylazoxymethanolacetate (MAM) model of schizophrenia (Gastambide et al., 2012;and see Vinson and Conn, 2012 for a review).

2.5. Other modulators

There are numerous modulators that can regulate NMDAR func-tion via depolarization (to relieve the Mg2þ block and thereby facil-itate the Hebbian depolarization). Regulation can also be viaintracellular signaling pathways, as exemplified by mGluRs andmAChRs. The former is a regulation that can, inprinciple, occurduringthe synaptic release of L-glutamate and, as such, can contribute to theproperty of cooperativity. Acetylcholine represents one of potentiallymany neurotransmitters and neuronal regulators that may regulate

NMDAR function in an associative manner. As discussed later (see3.6.1), other G-protein-coupled receptors (GPCRs; e.g. pituitary ade-nylate cyclase activatedpeptide 1 receptors, PAC1Rs) anddopamine 1receptors (D1Rs) have also been implicated in the subtype-specificmodulation of NMDARs via Src family kinases (Yang et al., 2012).These properties may therefore be exploited physiologically duringthe execution of cognitive processes.

3. Direct modulation

3.1. Antagonists

Consistent with the idea that NMDAR-LTP is important forlearning and memory, NMDAR antagonists have been found, innumerous investigations, to impair these processes. However,NMDAR antagonists can also be cognitively enhancing undercertain circumstances. The most notable example of this is mem-antine, a substance that is used in the treatment of Alzheimer’sdisease where it has a modest effect in delaying the decline incognitive function (Danysz and Parsons, 2003).

One way in which NMDAR antagonists may be able to enhancecognition is by selectively inhibiting the “pathological activation”while preserving the “physiological activation” of NMDARs. Thisprinciple was first demonstrated in a simple slice experiment inwhich Mg2þ was removed from the perfusing solution (Coan et al.,1989). This treatment led to the inhibition of LTP. Under theseconditions, addition of the specific competitive NMDAR antagonistAP5 was able to fully restore the ability to induce LTP. This was


because AP5 was able to block the aberrant activation of NMDARscaused by the removal of Mg2þ but during tetanic stimulationsufficient glutamate release occurred to outcompete the AP5 toactivate NMDARs appropriately to enable the induction of LTP.These results are re-plotted and represented schematically in Fig. 3.

This mechanism (block of pathological but not physiologicalNMDAR activation) is the rationale behind the cognitive enhancingeffects of memantine. Indeed, it was shown that memantine could,like AP5, restore the loss of LTP resulting from treatment with a lowMg2þ solution (Frankiewicz and Parsons, 1999). With memantinethe mechanism is slightly different since it is a fast, voltage-dependent channel blocker (Bresink et al., 1996; Frankiewiczet al., 1996). Therefore memantine suppresses the pathologicalactivation of NMDARs by occupying the channel but its block isrelieved by the Hebbian depolarization during the induction of LTP(Fitzjohn et al., 2008).

Along the same lines, the pathological activation of NMDARsmay be limited, without greatly affecting its physiological activa-tion, by increasing the Mg2þ concentration. This strategy has alsoproven effective and so Mg2þ can be considered a cognitiveenhancing agent (Slutsky et al., 2010). This principle can, of course,be extended to other types of NMDAR antagonists and compoundsthat regulate NMDAR function indirectly, such as mGlu5 receptornegative allosteric modulators. With respect to NMDAR antago-nists, there is evidence to suggest that compounds selective for

Fig. 3. Inappropriate activation of NMDARs inhibits LTP. The panels show data (left panel; r(right) under four experimental conditions (from top to bottom): in 1 mM Mg2þ (grey shadaddition of either 20 mM or 200 mM D-AP5 in Mg2þ-free medium (green shading and circactivation of NMDARs except during the induction stimulus (time of delivery of the tetanus isthe recording period and this inhibits the generation of LTP. A low concentration of D-AP5 noL-glutamate during high frequency stimulation. However, a high concentration of D-AP5 inh

GluN2B may enhance cognition and their possible use in Alz-heimer’s disease is under investigation (see Mony et al., 2009).

3.2. Glycine site

The co-agonist role of glycine or a glycine-like substance, such asD-serine, for the NMDAR channel complex was discovered byJohnson and Ascher (1987) who initially hypothesized an allostericsite that positively modulates the probability of channel opening.This initial observation was quickly followed by demonstrations ofselective functional antagonists at the glycine site (HA-966: Fletcherand Lodge, 1988; Foster and Kemp, 1989), (7-chlorokynurenic acid:Kemp et al., 1988) and (1-aminocyclobutane-1-carboxylate: Hoodet al., 1989). The absolute requirement for occupation of theglycine-site was confirmed by Kleckner and Dingledine (1988) bymeticulous elimination of glycine from the extracellular medium.Full activation of NMDARs requires agonist binding at two glycineand twoglutamate receptors on the tetrameric complex (Benvenisteand Mayer, 1991; Clements and Westbrook, 1991). Site directedmutagenesis of the GluN1 subunit determined GluN1 as the site ofglycine’s action (Kuryatov et al., 1994: Wafford et al., 1995). Inter-estingly, theGluN3 subunits are also activated byglycine rather thanbyglutamate so that tetrameric GluN1/GluN3 receptors are putativeexcitatoryglycine receptors, not requiring the presence of glutamate(Chatterton et al., 2002; Madry et al., 2007).

eplotted from Coan et al., 1989) and schematics during baseline (centre) and a tetanusing and black circles), following perfusion with Mg2þ-free medium, and following theles). Calibration bar is 4 mV and 5 min. Optimal conditions for LTP requires minimalindicated by an arrow). By removing Mg2þ, NMDAR activation in enhanced throughoutrmalizes the situation by inhibiting spurious NMDAR activation, but is outcompeted byibits NMDARs during high frequency stimulation.


The apparent high affinity of glycine for this site (Johnson andAscher, 1987; Kleckner and Dingledine, 1988) and several experi-mental studies at the time (Fletcher and Lodge, 1988; Kemp et al.,1988; but see Thomson et al., 1989) indicated that the glycine sitewas likely to be fully occupied in vivo either by glycine itself or by D-serine which had been originally described as mimicking theactions of glycine (Johnson and Ascher, 1987). Further studies (e.g.Berger et al., 1998) suggested that at some locations in the centralnervous system (CNS) at least, as a result of the activity of highaffinity glycine transporters (GlyT-1; Supplisson and Bergman,1997), the glycine site is not fully saturated by glycine.

As a result of this incomplete occupancy, several potential strat-egies for enhancing NMDAR function, and hence putativelyimproving cognition, via the glycine site have emerged (Fig. 2). Mostobvious is exogenous administration of agonists and partial agonists.Access of exogenous glycine to synapses utilising NMDARs is,however, limited by GlyT-1 and inhibition of this transporter is,therefore, more likely to be successful in increasing glycine levels atthe NMDAR (Supplisson and Bergman,1997; Berger et al.,1998; Chenet al., 2003; Bergeron et al., 1998; Martina et al., 2004; Stevens et al.,2010). GlyT-1 inhibition has been shown to enhance LTP (Martinaet al., 2004; Manahan-Vaughan et al., 2008) and cognition in botha social recognition test (Shimazaki et al., 2010) and an attentionalset-shifting task (Nikiforuk et al., 2011). Some preliminary studies inschizophrenics indicate improved cognitive performance (Tsai et al.,1998, 2004; Lane et al., 2005; Heresco-Levy et al., 1996) but thedanger of side effects due to activation of strychnine-sensitiveinhibitory glycine receptors needs attention (Kopec et al., 2010).

Increasing extracellular levels of D-serine, which does not acti-vate the glycine inhibitory receptor, offers several approaches.Exogenous D-serine has been shown to enable LTP, when theglycine site is not fully occupied by glycine (Oliver et al., 1990;Bashir et al., 1990; Watanabe et al., 1992; Duffy et al., 2008).Endogenous D-serine, produced in astrocytes by serine racemasefrom L-serine and glycine, has been shown to be necessary for bothLTP and LTD (Yang et al., 2003, 2005; Mothet et al., 2006;Henneberger et al., 2010; Fossat et al., 2012). Age-related or geneticdeficiencies in serine racemase lead to reduced LTP and memorydisruption which can be reversed by exogenous D-serine adminis-tration (Mothet et al., 2006; DeVito et al., 2011).

A further potential means of enhancing D-serine levels is byinhibition of its catabolising enzyme, D-amino acid oxidase (DAAO).This strategy has received a boost from the finding that mutant micelackingDAAOshowenhancedhippocampal LTPand improvedMorriswater maze performance compared with normal mice (Maekawaet al., 2005). Furthermore there are growing genetic associationsbetween DAAO and schizophrenia, (for example Chumakov et al.,2002). Several DAAO inhibitors have been synthesised and assessedin models of schizophrenia (see Ferraris and Tsukamoto, 2011) but itseems that DAAO inhibition alone does not raise D-serine levels asefficiently as exogenous administration of D-serine (see Smith et al.,2010). In support of this, Strick et al. (2011) found that DAAO inhibi-tion did not significantly affect either brain levels of D-serine, exceptin the cerebellum, or performance in cognitive behavioural assaysalthough there was an increase in hippocampal theta rhythm.

Enhancement of NMDA activity via the glycine site remains anattractive therapeutic possibility. As occupancy of this sitedecreases with old age, some combination of exogenous adminis-tration of D-serine, inhibition of GlyT-1 and inhibition of DAAOmayprove therapeutically successful.

3.3. Polyamines

Endogenous polyamines, such as spermine, have been shown topotentiate the activity of agonists on NMDARs (Williams, 1994a).

This potentiation is thought to be mediated by (i) glycine-dependent, (ii) voltage-dependent and (iii) glycine-and voltage-independent effects of spermine. The glycine-dependent effect isobserved in GluN2A or GluN2B containing NMDARs and is thoughtto be due to an increase in the affinity of glycine for the receptor.The presence of exon 5 in the N-terminal domain (NTD) of GluN1does not affect the glycine-dependent effect nor does extracellularpH (Williams, 1997). The glycine-independent effect refers to theability of spermine to enhance NMDAR currents evoked by satu-rating concentrations of glycine and glutamate. Tonic inhibition ofNMDARs by protons can be relieved by stimulation by spermine(Traynelis et al., 1995). This effect is only observed in GluN1/GluN2Bcontaining NMDARs and only if the NTD of the GluN1 subunit doesnot contain the exon-5 insert. Spermine has a weaker potentiatingeffect at subsaturating concentrations of glutamate due to its effectof lowering sensitivity of GluN1/GluN2B-containing NMDARs toglutamate (Williams, 1994a).

3.4. Neurosteroids

Endogenous neurosteroids have numerous actions in the brainincluding modulation of GABARs and NMDARs (Korinek et al.,2011). Pregnanolone and allopregnanolone, like progesterone,potentiate the actions of GABARswithminimal inhibitory effects onNMDAR function, which may underlie their anaesthetic actions(Selye,1941). Pregnanolone sulfateweakly inhibits both GABAR andNMDAR actions whereas pregnenolone sulfate (PS) stronglypotentiates NMDAR function (Fig. 2) and weakly inhibits GABAergicactivity. Other neurosteroids related to pregnenolone have similarbut in general less efficacious profiles.

PS, which is synthesized in brain tissue (Corpéchot et al., 1983),is then the neurosteroid of interest for potentiating NMDAR func-tion. PS, first described as a positive and selective allostericmodulator of NMDARs on chick spinal neurons (Wu et al., 1991) andhippocampal neurons (Bowlby, 1993), was shown to enhancelearning and memory (Flood et al., 1992; Mayo et al., 1993). It nowappears that its actions are quite complex with both inhibitory andfacilitatory sites on NMDARs (Park-Chung et al., 1997; Horak et al.,2004, 2006; Kostakis et al., 2011; Cameron et al., 2012). In GluN2Aor GluN2B subunit containing NMDARs, the facilitatory sitepredominates whereas, on those with GluN2C or GluN2D, inhibi-tion by PS predominates (Kostakis et al., 2011; Cameron et al.,2012). An earlier study suggested selective effects of PS and otherneurosteroids (but not anabolic androgenic steroids) on GluN2Brather than GluN2A containing receptors (see Elfverson et al., 2011).These PS binding sites are likely to be in the M3-M4 extracellularloop (S2 domain) of the GluN2 subunits, close to the proton site(Jang et al., 2004; Kostakis et al., 2011). A further complication isthat positive modulation of NMDARs by PS has been reported to bephosphorylation state dependent (Petrovic et al., 2009).

Enhanced NMDAR function underlies enhanced LTP at CA1synapses in the presence of PS (Sliwinski et al., 2004; Sabeti et al.,2007) and PS alone is able to induce long lasting potentiation (LLP)of synaptic efficacy at granule cell synapses (Chen et al., 2007). Inthis PS-induced LLP, the LTD-LTP induction curve is shifted to theleft so that lower stimulus frequencies are needed to induce thesetwo forms of plasticity (Chen et al., 2010). Levels of this endogenousneurosteroid decline with age in parallel with cognitive decline(Flood et al., 1995; Vallee et al., 1997). This decline in performancein the water maze task can be reversed by exogenous administra-tion of PS (Vallee et al., 1997). PS has also been claimed to reducethe amnesic effects of stress (Reddy and Kulkarni, 1998) andimprove cognition in schizophrenics (reviewed by Marx et al.,2011).

Fig. 4. Sites of intracellular modulation of NMDARs. Schematic representation of thedistribution of selected posttranslational regulatory sites on the intracellular C-terminal domains of GluN1, GluN2A and GluN2B NMDAR subunits. Serine (S) phos-phorylation sites: GluN1-S890, GluN1-S896, GluN1-S897, GluN2B-S1303, GluN2B-S1323,GluN2B-S1480 (Chung et al., 2004; Leonard and Hell, 1997; Liao et al., 2001; Liu et al.,2006; Sánchez-Pérez and Felipo, 2005; Sanz-Clemente et al., 2010; Scott et al., 2001,2003; Tingley et al., 1997). Tyrosine (Y) phosphorylation sites: GluN1-Y837, GluN2A-Y842 GluN2A-Y1336, GluN2A-Y1387, GluN2B-Y1336, GluN2B-Y1472 (Lau and Huganir, 1995;Moon et al., 1994; Nakazawa et al., 2001; Vissel et al., 2001; Yang and Leonard, 2001).Cysteine (C) Palmitoylation sites: GluN2A-C848, GluN2A-C853, GluN2A-C870, GluN2A-C1214, GluN2A-C1217, GluN2A-C1236, GluN2A-C1239, GluN2B-C849, GluN2B-C854, GluN2B-C871, GluN2B-C1215, GluN2B-C1218, GluN2B-C1242, GluN2B-C1239, GluN2B-C1245 (Hayashiet al., 2009). Calpain cleavage sites: GluN2A-1279, GluN2A-1330, GluN2Bw1030(approximately) (Dong et al., 2006; Guttmann et al., 2001; Simpkins et al., 2003; Doshiand Lynch, 2009). See text for further details (3.6. Intracellular modulation ofNMDARs).


Dehydroepiandrosterone sulfate (DHEAS), itself synthesizedfrom PS, also potentiates NMDARs and enhances LTP (Randall et al.,1995; Chen et al., 2006; for review see, Dubrovsky, 2005). Inter-estingly, inhibition of the synthesis of PS and DHEAS in hippo-campal slices reduces NMDAR function and LTP induction,suggesting a local ongoing synthesis of these neurosteroids (Tanakaand Sokabe, 2012).

3.5. Histamine and ATP

Histamine has been shown to potentiate agonist stimulatedeffects on recombinant NMDARs containing GluN1/GluN2B but notthose containing GluN2A or GluN2C subunits (Williams, 1994b).The effect was dependent on high agonist concentrations and didnot occur in NMDARs containing GluN1 subunits with the exon 5insert in the NTD.

Adenosine triphosphate (ATP) inhibits recombinant NMDARscontaining GluN1/GluN2A or GluN1/GluN2B subunits at lowagonist concentrations but at saturating agonist concentrations actsas a potentiator (Kloda et al., 2004). In contrast, ATP potentiatesNMDARs containing GluN1/GluN2C even at nonsaturating agonistconcentrations. ATP has been proposed to compete with glutamatefor its binding site and this may explain why high agonistconcentrations are required to reveal the potentiating effect of ATPon GluN1/GluN2A or GluN1/GluN2B.

3.6. Intracellular modulation of NMDARs

The function of NMDARs, like other iGluRs, is also regulated byposttranslational modifications (e.g. phosphorylation, palmitoyla-tion, ubiquitination, proteolytic cleavage by calpain) and by proteinbinding partners, Here we overview some of the complex intra-cellular pathways that are key modulators of NMDAR function.These regulatory mechanisms could in principle be targetedpharmacologically.

3.6.1. Functionally significant key phosphorylation sites of NMDARsubunits

The function and subcellular distribution of NMDARs aredifferentially regulated by phosphorylation of specific serine (S)/threonine (T) and tyrosine (Y) amino acid residues in the intracel-lular C-terminal domains of various subunit proteins (Salter et al.,2009; Traynelis et al., 2010). Protein kinases that catalyse phos-phorylation and phosphoprotein phosphatases that catalysedephosphorylation are recruited to NMDARs via interactions withpostsynaptic density protein 95 (PSD95), A-kinase anchoringproteins (AKAP79/150) and yotiao (Colledge et al., 2000; Klaucket al., 1996; Salter et al., 2009; Westphal et al., 1999). This com-partmentalisation is likely to increase the selectivity, efficiency andspeed of phosphorylation and dephosphorylation events. In thissection, we highlight some of the main functional changesproduced by the phosphorylation of key sites in core NMDARsubunit proteins. See recent reviews for a more extensive list ofpossible, but not fully verified NMDAR phosphorylation sites (Salteret al., 2009; Traynelis et al., 2010).

In the alternatively spliced C-terminal C1-cassette of GluN1,protein kinase C (PKC) phosphorylates serine residues GluN1-S890and GluN1-S896 (Tingley et al., 1997) (Fig. 4). In contrast, theneighbouring GluN1-S897 is phosphorylated by cyclic AMP-dependent protein kinase A (PKA; Tingley et al., 1997) (Fig. 4).Phosphorylation of these sites regulates cell surface expression andclustering of NMDARs (Crump et al., 2001; Ehlers et al., 1995; Fonget al., 2002; Scott et al., 2003; Tingley et al., 1997) and may affectchannel function by modulating the inhibitory interaction betweenGluN1 and calmodulin (Ehlers et al., 1996; Hisatsune et al., 1997).

GluN1-S890 and GluN1-S896 are preferentially phosphorylated byPKCg and PKCa, respectively (Sánchez-Pérez and Felipo, 2005)(Fig. 4). Phosphorylation of the GluN1-S890 but not GluN1-S896 orGluN1-S897 residues facilitates rapid dispersal of synaptic NMDARs(Tingley et al., 1997). Activation of group I mGluRs by DHPGincreases GluN1-S890 but not GluN1-S896 phosphorylation. Surfaceexpressed GluN1 proteins are phosphorylated at S890 but not at S896(Sánchez-Pérez and Felipo, 2005). The dual PKC/PKA phosphory-lation of GluN1-S896/GluN1-S897 promotes NMDAR trafficking from


the endoplasmic reticulum to the cell surface (Scott et al., 2001,2003).

The C-terminal domains of GluN2A and GluN2B are substratesfor Ca2þ/calmodulin-dependent protein kinase (CaMKII; Omkumaret al., 1996), PKC and PKA (Leonard and Hell, 1997; Liao et al., 2001,Fig. 4). NMDAR-PSD95/SAP102 interactions are disrupted by caseinkinase II (CK2)-mediated GluN2B-S1480 phosphorylation (Chunget al., 2004). This activity-dependent process is thought to be animportant component of the developmental switch from GluN2B-to GluN2A-containing NMDARs at synapses (Sanz-Clemente et al.,2010). Phosphorylation of GluN2B-S1303 and GluN2B-S1323 by PKCpotentiates GluN2B-containing NMDAR current (Liao et al., 2001,Fig. 4). GluN2B-S1303 may also be phosphorylated by CaMKII, whichaffects the receptorekinase interaction (Liu et al., 2006). In GluN2C,S1230 is phosphorylated by both PKA and PKC (Chen et al., 2006).Phosphomimetic mutation of GluN2C-S1230 accelerates channelkinetics by increasing the speed of both the rise and decay ofNMDA-evoked currents (Chen et al., 2006). Increased PKA activitycan facilitate the induction of LTP by increasing the Ca2þ perme-ability of NMDARs in dendritic spines (Skeberdis et al., 2006).

Several potential sites of tyrosine kinase phosphorylation havebeen identified in GluN1, GluN2A and GluN2B (Moon et al., 1994;Lau and Huganir, 1995, Fig. 4). Disruption of GluN1-Y837 andGluN2A-Y842, by site-directed mutagenesis, prevented use-dependent desensitization of GluN1/GluN2A NMDARs (Visselet al., 2001). However, the GluN1 intracellular C-terminus doesnot appear to be tyrosine phosphorylated in neurons (Lau andHuganir, 1995). GluN2A-Y1387 and GluN2B-Y1472 are major sites ofphosphorylation by Src-family kinases (Nakazawa et al., 2001; Yangand Leonard, 2001, Fig. 4). Tyrosine phosphorylation potentiatesthe NMDAR ion channel resulting in increased Ca2þ currents (Aliand Salter, 2001) and has been implicated in the regulation of theinternalization of NMDARs (Vissel et al., 2001; Li et al., 2002).Increased GluN2B-Y1472 phosphorylation promotes the synaptictargeting of NMDARs (Prybylowski et al., 2005). Furthermore, Src-mediated upregulation of NMDARs is thought to play an impor-tant role in LTP of CA1 neurons (Groveman et al., 2012; Ohnishiet al., 2011; Trepanier et al., 2012). This is supported by thefinding that the level of GluN2B-Y1472 phosphorylation increasesfollowing tetanic stimulation in the CA1 region of the hippocampus(Nakazawa et al., 2001). The striatal-enriched tyrosine phosphatase(STEP) dephosphorylates GluN2B-Y1472 (Braithwaite et al., 2006;Pelkey et al., 2002; Snyder et al., 2005) and also inactivates Fyn(Nguyen et al., 2002), therefore both directly and indirectlydownregulate synaptic NMDAR expression. Furthermore, synapticand extrasynaptic NMDARs are differentially phosphorylated atGluN2B-Y1472 and GluN2B-Y1336, respectively (Gobel-Goody et al.,2009), suggesting that modulation of NMDAR tyrosine phosphor-ylation affects receptor retention and translocation betweensynaptic and extrasynaptic sites (Gladding and Raymond, 2011).

A recent study raised the intriguing possibility that the directionof synaptic plasticity in CA1 neurons is determined by differentclasses of GPCRs that differentially target tyrosine phosphorylationsites in GluN2A and GluN2B NMDAR subunits (Fig. 4) via selectiveactivation of Src and Fyn kinases (Yang et al., 2012). The Gaq-coupled pituitary adenylate cyclase activating peptide 1 receptors(PAC1Rs) selectively enhanced the activity of GluN2A-containingNMDARs through the activation of Src kinase. In contrast, theGas-coupled dopamine 1 receptors (D1R) enhanced GluN2B-containing NMDARs via selective activation of Fyn (Yang et al.,2012). While PAC1R lowered the threshold for LTP, D1R enhancedLTD indicating that NMDAR-mediated metaplasticity is gated byGPCRs (Yang et al., 2012). These findings are consistent with thenotion that the balance between the activities of GluN2A- andGluN2B-containing NMDARs is a key determinant of the direction

of synaptic plasticity (Cho et al., 2009; Fox et al., 2006; Liu et al.,2004; Massey et al., 2004) and GPCRs can provide a mechanismbywhich other neuromodulators affect NMDAR function (Section 2.Indirect modulation). Compounds acting via GPCRs to alter thetyrosine phosphorylation status of NMDARs, offer a wide spectrumof possibilities for modulating cognitive function.

3.6.2. Palmitoylation of NMDARsPalmitatic acid is a saturated fatty acid that is highly abundant in

the CNS. Palmitate forms a covalent attachment to proteins viathioester bonds at cysteine (C) residues. This modification is labile,reversible and dynamically regulated by neuronal activity (Hayashiet al., 2009). GluN2A and GluN2B have two potential palmitoylationsites in their C-terminal domains (Cys clusters I and II; Fig. 4,Hayashi et al., 2009). Palmitoylation of Cys cluster I controls stablesynaptic expression and constitutive internalization of surfaceNMDARs. De-palmitoylation of Cys cluster II regulates surfacedelivery of NMDARs (Hayashi et al., 2009). Decreased GluN2B pal-mitoylation at both clusters is likely to reduce synaptic NMDARpopulation and increase extrasynaptic NMDAR numbers (Gladdingand Raymond, 2011). Therefore, palmitoylation of GluN2 subunitsalso contributes to regulation of NMDAR trafficking and affectsbrain function.

3.6.3. Ubiquitination of NMDARsUbiquitin is a small (76 amino acid containing) protein that

covalently attaches to specific lysine (K) residues in substrateproteins in an ATP-dependent, sequential action of three classes ofenzymes, E1-3 (Mabb and Ehlers, 2010). The number and subunitcomposition of synaptic NMDARs are regulated by activity-dependent protein degradation through the ubiquitin-proteasomesystem (Ehlers, 2003). Increased synaptic activity leads to upre-gulation of GluN2A, PSD95 and Homer protein expression anddownregulation of GluN1, GluN2B and Shank (Ehlers, 2003). Thesechanges are blocked by proteosomal inhibitors (Ehlers, 2003). Mindbomb-2 (Mib2) E3 ubiquitin ligase interacts with and ubiquitinatesthe GluN2B NMDAR subunit in a Fyn phosphorylation-dependentmanner (Jurd et al., 2008). These findings indicate that ubiquiti-nation is an important mechanism for the removal and degradationof NMDARs that results in dynamic regulation of synaptic strengthin response to activity.

3.6.4. Proteolytic cleavage of NMDAR subunits by calpainThe Ca2þ-activated protease calpain cleaves the C-terminal

domains of GluN2A-C subunits, but not GluN1 (Dong et al., 2006;Guttmann et al., 2001; Simpkins et al., 2003; Doshi and Lynch,2009, Fig. 4). While the proteolytic truncation of NMDAR subunitsremoves regulatory and proteineprotein interaction sites andreduces synaptic activity, basic ion channel gating and key phar-macological properties are not affected (Guttmann et al., 2001;Simpkins et al., 2003). Therefore, it is plausible that calpain cleavedNMDARs remain functional on the cell surface at extrasynaptic sites(Gladding and Raymond, 2011).

3.6.5. Protein binding partners of NMDARsLike other iGluRs, NMDARs also interact with a wide range of

cytoskeletal, scaffolding and signalling proteins (e.g. a-actin-2, AP2,calmodulin, CaMKII, CARPI, COPII, GPS2, LIN7, MAP1S, PACSIN1,plectin, PSD95, RACK1, SALM1, SAP97, SAP102, S-SCAM; Trayneliset al., 2010). An auxiliary subunit, Neto1, has also been describedfor NMDARs (Ng et al., 2009). Neto1 interacts with an extracellulardomain of GluN2 as well as through an intracellular interactionwith PSD95. Loss of Neto1 in transgenic mice preferentially resultsin a loss of synaptic GluN2A expression, with only a modest impacton GluN2B expression, which leads to impaired hippocampal LTP


and hippocampal-dependent learning and memory (Ng et al.,2009).

At synapses, NMDARs are stabilised by interaction with PSD95(Roche et al., 2001; Li et al., 2003). The association of NMDARs withPSD95 and their subsequent endocytosis is regulated by tyrosinephosphorylation. Phosphorylation of GluN2B-Y1472 interferes withbinding to PSD95 and promotes clathrin-dependent endocytosis bypromoting the binding of AP2 to GluN2B. Dephosphorylation ofGluN1-Y837 and GluN2A-Y842 might affect AP2 binding, promotingclathrin-dependent endocytosis in a similar way (Vissel et al.,2001). There is evidence that the synaptic activation of mAChRsleads to a reduction in the surface expression of synaptic NMDARsvia the recruitment of hippocalcin, which triggers the exchange ofPSD-95 for AP2 to promote endocytosis (Jo et al., 2010).

Intradendritic trafficking of GluN2B subunits requires them toassociate with the motor protein KIF17 through LIN10 (Guillaudet al., 2003). Within the PSD, NMDARs are linked by a-actin andspectrin to f-actin, which associates with myosin and might bedynamically regulated by MLCK (myosin light chain kinase; Leiet al., 2001). Synaptic GluN2A containing NMDARs seem to beimportant for LTP and extrasynaptic GluN2B-containing receptorsare involved in LTD (Cull-Candy et al., 2001). In adult neocorticalslices de novo LTD induction is enhanced by blockage of glutamateuptake, indicating that the diffusion of glutamate to extrasynapticGluN2B containing NMDARs triggers LTD (Massey et al., 2004).Furthermore, LTD can be induced after blockade of synapticNMDARs (Massey et al., 2004). Therefore, NMDAR interactions,localisation and targeting are crucial determinants of synapticplasticity and consequently cognition.

4. Recently discovered NMDAR PAMs

4.1. Phenanthrene derivatives

A series of 9-substituted phenanthrene-3-carboxylic acidderivatives has been reported to potentiate NMDAR activity withdifferent patterns of GluN2 subunit selectivity (Costa et al., 2010). Inan electrophysiological assay on GluN1/GluN2 NMDAR subtypesexpressed in Xenopus oocytes, the 9-iodo derivative, UBP512,weakly potentiated GluN2A, had little or no effect on GluN2B andinhibited GluN2C- and GluN2D-containing NMDARs. When testedin the presence of 30-fold higher concentrations of glycine andglutamate UBP512 displayed an enhanced potentiating effect onGluN2A. Potentiation of GluN1/GluN2A by UBP512 due to chelationof Zn2þ, resulting in reversal of Zn2þ inhibition, was ruled out in thisstudy (Costa et al., 2010). The 9-cyclopropyl derivative, UBP710(Fig. 2), potentiated GluN2A and GluN2B but had inhibitory activityon GluN2C or GluN2D-containing NMDARs, when tested at higherconcentrations. The 9-i-hexyl derivative, UBP646, however, actedas a universal potentiator on recombinant NMDARs containingGluN2A-D, displaying the greatest potentiating effect on GluN2D.

The NTD is not necessary for the potentiating effect of UBP512 orUBP710, as these compounds still caused potentiation when testedon GluN1/GluN2A receptors without NTDs (Costa et al., 2010).Chimeric receptor studies were used to investigate whether the S1and S2 regions of the ligand binding domain (LBD) of GluN2Awereinvolved in the NMDAR potentiating activity of UBP512 and UBP710(Costa et al., 2010). These studies relied on the different modes ofaction of UBP512 and UBP710 on GluN2 subunits, i.e., the potenti-ation of GluN2A and inhibition of GluN2C. Swapping the S1 domainof GluN2A with the S1 domain of GluN2C did not affect thepotentiating effect of UBP512 and UBP710. However, swapping theS2 domain of GluN2Awith the S2 domain of GluN2C converted thecompounds to inhibitors, suggesting that they may be binding to

the S2 domain or that the S2 domain is involved in the transductionof the potentiating effect.

Examination of the crystal structure of the LBDs of GluN1/GluN2A suggested that Y535 in GluN1 can play a positive allostericmodulatory role by interacting with hydrophobic residues in thedimer interface, thereby stabilizing the dimer interface and slowingdeactivation (Furukawa et al., 2005). In support of a role for Y535 incontrolling deactivation, the Y535L mutant showed a modestincrease in the rates of glycine and glutamate deactivation, whereasthe Y535F mutant showed slightly slower deactivation rates(Furukawa et al., 2005). Given that the S2 domain of GluN2A isrequired for the potentiating effect of UBP512 and UBP710 onGluN2A, it is reasonable to suggest that these compounds arebinding at the GluN1/GluN2A dimer interface to block desensiti-zation and/or slow deactivation, perhaps by stabilizing the inter-action of Y535 with the hydrophobic site in the dimer interface orby contributing additional stabilization to that provided by Y535.However, it is also possible that these compounds are bindingwithin or in close proximity to the transmembrane region leadingto stabilization of the open channel conformation. More work isrequired to identify the precise binding site(s) and mechanism ofaction of the UBP compounds.

4.2. Naphthalene derivatives

Anaphthalene derivative, 3,5-dihydroxynaphthalene-2-carboxylicacid, UBP551 showed a selective potentiating effect on GluN2D andinhibitory activity on GluN2A-C (Costa et al., 2010). The concentrationresponse curve for the potentiating activity of UBP551 on GluN2D isbell shaped, greatest potentiation was observed at 30 mM and poten-tiation was reduced at higher concentrations. UBP551 is uniqueamongst the recently reported potentiators in that it has differentialactivity on GluN2C and GluN2D. The mechanism underlying thepotentiating effect of UBP551 on GluN2D is unknown but itmay differfrom that of the structurally dissimilar phenanthrene basedpotentiators.

4.3. Coumarin derivatives

The coumarin derivative, 6-bromo-4-methylcoumarin-3-carboxylic acid, UBP714 (Fig. 2), has been shown to have a weakpotentiating effect on recombinant GluN2A-, GluN2B- and GluN2D-containing NMDARs (Fig. 5 and Irvine et al., in press). UBP714potentiated field excitatory postsynaptic potentials (fEPSPs) medi-ated by NMDARs but not those due to AMPARs in the CA1 region ofthe hippocampus (Fig. 5 and Irvine et al., in press). Interestingly, ananalogue of UBP714, without the 4-methyl group, 6-bromocoumarin-3-carboxylic acid, UBP608, was a moderatelypotent inhibitor of GluN1/GluN2A with an IC50 value 18.6 mM,suggesting that the methyl group of UBP714 is necessary forpotentiating activity (Costa et al., 2010; Irvine et al., in press).

4.4. Isoquinoline derivatives

A novel structural class of NMDAR potentiator, CIQ ((3-chlorophenyl)(6,7-dimethoxy-1-((4-methoxyphenoxy)methyl)-3,4-dihydroisoquinolin-2-(1H)-yl)methanone, Fig. 2) has been reportedto selectively potentiate NMDARs containing GluN2C or GluN2Dsubunits (Mullasseril et al., 2010). CIQ was found to potentiaterecombinant triheteromeric GluN1/GluN2A/GluN2C or GluN1/GluN2A/GluN2D NMDARs, suggesting that only one GluN2C orGluN2D subunit is required for the potentiating effect. Single channelanalysis of the effect of CIQ on GluN1/GluN2D suggested that thepotentiating effect was due to an increase in channel openingfrequency, without altering mean open time. CIQ also potentiated

Fig. 5. UBP714 potentiates NMDAR responses A. Data (n ¼ 4, mean � S.E.M.), showingthat UBP714 potentiates NMDAR-mediated GluN1/GluN2A (17 � 2%, 2A), GluN1/GluN2B (14 � 1%, 2B) and GluN1/GluN2D (4 � 1%, 2D) responses in Xenopus laevisoocytes (reprinted from Irvine et al., in press). The trace to the right shows that 100 mMUBP714 (grey bar) potentiates GluN1/GluN2A NMDAR response, which was evoked byapplying 10 mM glutamate and 10 mM glycine (black bar). B. Data (n ¼ 10) showing thatUBP714 potentiates pharmacologically isolated NMDAR-mediated f-EPSPs (inset) inhippocampal slices from adult rat (19 � 2%, 1-h after the start of application of 100 mMUBP714, reprinted from Irvine et al., in press).


NMDAR currents mediated by GluN2D expressed in subthalamicneurons. CIQ appears to have different structural requirements for itspotentiatingeffect onNMDARs compared to theUBP compounds andPS. Chimeric receptor and point mutation studies suggest that thelinker between the NTD and the LBD and T592 in the M1 region ofGluN2D are required for the potentiating effect of CIQ. This, coupledwith theminimal effect of CIQ on NMDAR deactivation, suggests thatthe dimer interface is not a likely site for CIQ binding and that thepotentiating effect is occurring by a different mechanism to thatobserved for UBP compounds.

5. Concluding remarks

This review indicates a number of ways in which NMDARfunction could be modulated. NMDARs are ubiquitously expressedthroughout the CNS and as such are involved in all functions ofneural circuits of the brain and spinal cord. The complexity andmultiplicity of NMDARs, its heteromeric structurewith intracellularsites for modulation of function and its subtypes offer numerousopportunities for therapeutic interventions. Because of the widelyaccepted role of NMDARs in plasticity and memory, the obviousapproach for cognitive enhancement is potentiation of NMDARfunction. However, given the complex roles of NMDARs in synaptictransmission and bidirectional synaptic plasticity the

normalization of function could be a better strategy. Putativecompounds for considerationwill need to have subtle effects; over-stimulation of NMDARs will inter alia likely lead to exacerbation ofpain, hyperexcitability and neurodegeneration. Subunit selectivityand limited efficacy may therefore be desirable properties. Newcompounds with direct but allosteric and specific effects on theNMDAR subunits may offer the most fruitful approach.

Acknowledgements

This work was supported by the MRC (Grants G0601509 andG061812), BBSRC (Grants BB/F012519/1 and BB/J015938/1) and theNIH (Grant MH60252).

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