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Levin ED, Buccafusco JJ, editors. Animal Models of Cognitive Impairment. Boca Raton (FL): CRC Press/Taylor & Francis; 2006.

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Animal Models of Cognitive Impairment.

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Chapter 4Involvement of the NMDA System in Learning and Memory


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Since its discovery in the early 1950s, the N-methyl-D-aspartate (NMDA) receptor system in the brain has been implicated in many fundamental functions, including neuronal plasticity, neurotoxicity, learning, and memory (Riedel et al., 2003). The aim of this chapter is to summarize the current findings on the role of glutamate-receptor systems in learning and memory in different animal models and humans. The structure, localization, and pharmacology of these receptors will not be discussed in this chapter. For those who are interested in these particular topics, we refer them to an excellent recent review (Riedel et al., 2003).

Animal Studies

Researchers have provided increasing evidence that the NMDA-receptor systems generally, and glutamate-mediated long-term potentiation (LTP) in particular, may play a crucial role in the processes of learning and memory formation. NMDA receptors in the brain have been implicated and been shown to play a crucial role in various types of learning. These receptors have been demonstrated to be involved in Pavlovian fear conditioning (Xu et al., 2001), eyeblink conditioning (Thompson and Disterhoft, 1997), spatial learning (Morris et al., 1986; Shimizu et al., 2000; Tsien et al., 1996), working and reference memory (Levin et al., 1998; May-Simera and Levin, 2003), place preference (Swain et al., 2004), passive-avoidance learning (Danysz et al., 1988), olfactory memory (Si et al., 2004; Maleszka et al., 2000), and reversal learning (Harder et al., 1998).


It has been suggested that the activation of the NMDA receptor is required for long-term potentiation (LTP) in the hippocampus, amygdala, and medial septum (Izquierdo, 1994; Rockstroh et al., 1996; Scatton et al., 1991). This mechanism has been implicated in memory formation; the involvement of the glutamate-receptor system and LTP is strongly linked to new learning and memory in animal models (Lozano et al., 2001; Scheetz and Constantine-Paton, 1994; Tang et al., 1999, 2001; Wong et al., 2002). Both lesion studies and pharmacological manipulations in experimental animals suggest that the NMDA-receptor system may be important in the induction of memory formation, but not for the maintenance of memories (Constantine-Paton, 1994; Izquierdo, 1991; Izquierdo and Medina, 1993; Liang et al., 1993; Quartermain et al., 1994; Rickard et al., 1994). Indeed, it has been shown that NMDA-receptor blockade after learning a task had no effect on memory performance in humans, whereas blockade of receptors before learning resulted in memory impairment (Hadj Tahar et al., 2004; Oye et al., 1992; Rowland et al., 2005).

NMDA alone, systemically administered in rats, has been shown to potentiate cognitive functions (Hlinak and Krejci, 2002; Koek et al., 1990). A recent study (Hlinak and Krejci, 2003) investigated whether systemically administered NMDA can prevent amnesia induced by an NMDA antagonist dizocilpine (MK-801). Using a modified elevated plus maze paradigm, it was demonstrated that NMDA administered subcutaneously immediately after the acquisition session protected the mice against amnesia induced by MK-801 given shortly before the retention session.

Transgenic And Mutant Mice

Studying transgenic and mutant mice has provided more evidence in support of the involvement of the NMDA in cognition. Mutant mice lacking the NMDA-receptor subunit NR2A have shown reduced hippocampal LTP and spatial learning (Sakimura et al., 1995). Also, transgenic mice lacking NMDA receptors in the CA1 region of the hippocampus show both defective LTP and severe deficits in both spatial and nonspatial learning (Shimizu et al., 2000; Tsien et al., 1996). On the other hand, genetic enhancement of NMDA-receptor function results in superior learning and memory. Recently, in an interesting study, Tang et al. (2001) confirmed the role of the NMDA-receptor system in LTP in the hippocampus and in learning and memory. Using the NR2B transgenic (Tg) lines of mice, in which the NMDA-receptor function is enhanced via the NR2B subunit transgene in neurons of the forebrain, they demonstrated both larger LTP in the hippocampus and superior learning and memory in naïve NR2B Tg mice (Tang et al., 1999; Tang et al., 2001; Wong et al., 2002). In the novel-object recognition task, however, enriched NR2B Tg mice exhibited much longer recognition memory (up to 1 week) compared with that (up to 3 days) of naïve NR2B Tg mice. Together, these findings confirm and support the important role of the NMDA receptor in memory.

NMDA Antagonists

NMDA-receptor antagonists such as MK-801, ketamine, phencyclidine (PCP), 2-amino-5-phosphonopentanoate (AP5), and selective mGlu5-receptor antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) have been extensively used to study the role of NMDA in learning and memory. Both acute and subchronic administration of NMDA-receptor antagonists have been shown to impair performance on tasks that seem to depend upon hippocampal or amygdaloid functions (Izquierdo and Medina, 1993; Jentsch and Roth, 1999; Morris et al., 1986). These tasks include passive avoidance (Benvenga and Spaulding, 1988; Kesner and Dakis, 1993; Murray and Ridley, 1997; Venero and Sandi, 1997), acquisition of Morris water maze (Heale and Harley, 1990), and delayed alteration (Verma and Moghaddam, 1996).

The noncompetitive, highly specific N-methyl-D-aspartate NMDA-receptor antagonist dizocilpine (MK-801) (E. H. Wong et al., 1986) has been shown to induce dose-dependent impairment of learning and memory (Benvenga and Spaulding, 1988; Butelman, 1990; Carey et al., 1998; de Lima et al., 2005; Hlinak and Krejci, 1998, 2003; May-Simera and Levin, 2003; Murray and Ridley, 1997; Murray et al., 1995; Venero and Sandi, 1997). It has also been shown that MK-801 selectively disrupts reversal learning in rats using serial reversal tack (van der Meulen et al., 2003). Further, several studies have revealed that MK-801 administration impairs different aspects of learning and memory in the elevated plus maze in rodents (Hlinak and Krejci, 1998, 2000, 2002). Recently, the effects of NMDA-receptor blockade on formation of object-recognition memory were examined in rats. It was found that MK-801 impaired both short- and long- term retention of object-recognition memory when given either before or after training. These results suggest that NMDA-receptor activation is necessary for formation of object-recognition memory (de Lima et al., 2005). Amnesic effects of MK-801 in mice have also been reported. MK-801 injected intravenously in mice before a training trial in a passive-avoidance task produced an amnesic effect similar to that produced by the standard amnesic agent scopolamine, yet the potency of MK-801 was 40 times that of scopolamine. Effects of MK-801 on corticosterone facilitation of long-term memory have been examined in chicks. It has been shown that long-term memory formation for a weak passive-avoidance task in day-old chicks is facilitated by corticosterone administration (Venero and Sandi, 1997) and that intracerebral infusion of MK-801 prevents the facilitating effect of corticosterone when MK-801 is given before the training trial. These results support the view that corticosterone facilitates the formation of long-term memory in this particular learning model through the modulation of the NMDA-receptor system in the brain.

In addition to memory impairment, MK-801 has been shown to induce changes in motor activity (Ford et al., 1989). Therefore, it is important to know whether the MK-801 effects upon memory are secondary to its effect on motor disturbance. In an attempt to address this important issue, Carey et al. (1998) examined the effects of MK-801 upon retention of habituation to a novel environment and locomotor activity. It was demonstrated that a low dose of 0.1 mg/kg MK-801, which did not affect locomotor activity, severely interfered with retention of the novel environment. This observation suggests dissociation between the effects of MK-801 on memory and locomotor activity.

The eyeblink classical conditioning paradigm is an extensively used measure of associate learning and memory (Woodruff-Pak et al., 2000). The contribution of the NMDA-receptor system in the brain to classical eyeblink conditioning has been investigated pharmacologically in rabbits and mice. It has been shown that MK-801 slows the rate of acquisition during delay conditioning (Thompson and Disterhoft, 1997).

Using eyeblink classical conditioning in mice, Takatsuki et al. (2001) demonstrated the role of NMDA receptors in acquisition of the conditioned response (CR). Further, these researchers have shown that the contribution of these receptors to extinction is much smaller than their contribution to acquisition in mouse eyeblink conditioning. In these studies, it was shown that MK-801 impaired acquisition of the CR during mouse eyeblink conditioning in a task-dependent manner.

Learning impairments induced by glutamate blockade using MK-801 have also been reported in nonhuman primates. Acquisition and reversal learning of visual-discrimination tasks and acquisition of visuospatial discrimination tasks were assessed in marmosets using the Wisconsin General Test Apparatus. It was shown that MK-801 impaired acquisition of visuospatial (conditional) discrimination (Harder et al., 1998). Lesions of the fornix (Harder et al., 1996) or hippocampus (Ridley et al., 1988, 1995) have been shown to produce a specific and severe impairment on visuospatial tasks. Thus, it could be suggested that it is the effect of MK-801 on glutamatergic corticohippocampal projections that is responsible for the visuospatial impairment (Harder et al., 1998).

Selective impairment of learning and blockade of LTP by other NMDA-receptor antagonists has been reported. It has been shown that blockade of NMDA sites with the drug AP5 does not detectably affect synaptic transmission in the hippocampus, but prevents the induction of LTP. Interestingly, chronic intracerebroventricular infusion of D,L-AP5 (which blocks LTP in vitro and in vivo) selectively impaired the acquisition of place learning in the Morris water maze, a type of learning that is dependent on normal hippocampal functioning. These results further suggest that the NMDA-receptor system is involved in spatial learning and supports the hypothesis that LTP is involved in some forms of learning (Morris et al., 1986).

Recently, it was also demonstrated that MPEP at a relatively high dose, but not at low dose, impaired working memory and instrumental learning. MPEP administration also caused a transient increase in dopamine release in the prefrontal cortex and nucleus accumbens. MPEP exposure also augmented the effect of MK-801 on cortical dopamine release, locomotion, and stereotypy. Pretreatment with low (3 mg/kg) MPEP enhanced the detrimental effects of MK-801 on cognition (Homayoun et al., 2004). These results suggest that an mGlu5-receptor antagonist such as MPEP plays a major role in regulating NMDA-receptor-dependent cognitive functions.

To investigate the involvement of the NMDA receptors in different stages of memory consolidation, Tronel and Sara (2003) recently examined the effect of a competitive NMDA-receptor antagonist, 2-amino-5-phosphonovalerate (APV), on odor-reward associative learning in rats. It was shown that the blockade of NMDA receptors by APV injected intracerebroventricularly immediately after training induced a profound and enduring amnesia, but had no effect when the treatment was delayed 2 hours after training. More specifically, it was shown that the blockade of NMDA receptors in the prelimbic region of the frontal cortex, but not into the hippocampus, impaired memory formation of the odor-reward association in rats. These results confirm the role of NMDA receptors in the early stage of consolidation of a simple odor-reward associative memory and underlie the role of the frontal cortex in consolidation of long-term memory (Tronel and Sara, 2003).

There have also been reports of amnesia in passive-avoidance task induced by posttrial administration of APV into the hippocampus or the amygdala (Ferreira et al., 1992; Zanatta et al., 1996). However, in a recent study, Santini et al. (2001) demonstrated that the amnesia observed 24 hours after systemic administration of NMDA antagonist D(-)-3-(2-carboxypiperazine-4-yl)-propyl-1-phosphonic acid (CPP) was transient. The authors argue that the so-called rescued memory at 48 hours supports the existence of late waves of NMDA activity promoting memory consolidation.

Pretraining administration of NMDA-receptor antagonists has been shown to produce anterograde amnesia in Pavlovian fear conditioning (Kim et al., 1991; Xu and Davis, 1992), spatial learning (Hauben et al., 1999), and passive avoidance (Danysz et al., 1988). Intercranial administration of NMDA-receptor antagonist AP5, without impairing performance processes, produced anterograde amnesia when given before training in goldfish (Xu et al., 2001).

Phencyclidine (PCP), a noncompetitive NMDA-receptor antagonist, has been shown to produce both positive and negative symptoms of schizophrenia as well as cognitive defects in healthy humans (Javitt and Zukin, 1991; Tamminga, 1998). PCP has been used to further investigate the role of the NMDA-receptor system in learning and memory. The performance of rats and mice (Podhorna and Didriksen, 2005) in the Morris water maze and spatial continuous recognition memory task have all been shown to be impaired following acute PCP exposure. PCP-treated animals maintained the original learned rule, and they were only impaired in abolishing it and establishing a new rule. This suggests that acute PCP administration at doses of 1.0 and 1.5 mg/kg was able to significantly impair complex cognitive tasks without disrupting simple rule-learning parameters (Abdul-Monim et al., 2003). Recently, it was shown that repeated administration of PCP failed to produce enduring memory impairment in an eight-arm radial arm maze in rats or mice (Li et al., 2003).

Haloperidol failed to ameliorate the deficit in reversal task performance induced by PCP. In contrast, the new atypical antipsychotic ziprasidone produced a significant improvement in impairment of the reversal task performance induced by PCP (Abdul-Monim et al., 2003). Consistent with these findings, it has been demonstrated that in a novel objective recognition test, repeated administration of PCP significantly decreased exploratory preference in the retention test session but not in the training test session. PCP-induced deficits were significantly improved by subsequent sub-chronic administration of clozapine but not haloperidol (Hashimoto et al., 2005).

NMDA Transporter Inhibitors

Blockade of glutamate uptake by transporter inhibitors has also been used to study the role of NMDA in memory formation. Recently, it was demonstrated that pre-training injections of a glutamate-transporter inhibitor L-trans-2,4-PDC (L-trans-2,4-pyrrolidine dicarboxylate) had no effect on acquisition and short-term (1 h) memory but impaired long-term (24 h) associative olfactory memory in a dose-dependent manner in the honeybee. This effect was found to be transient, and amnesic animals could be retrained 48 h after injections (Maleszka et al., 2000). Using the same species, Si et al. (2004) examined the behavioral effects of L-trans-2,4-PDC and antagonists memantine (low affinity) and MK-801 (high affinity) on learning and memory. Consistent with previous findings (Maleszka et al., 2000), L-trans-2,4-PDC exposure induced amnesia in the honeybee. Similar to L-trans-2,4-PDC, both pretraining and pretesting injections of MK-801 led to an impairment of long-term (24 h) memory, but had no effect on short-term (1 h) memory of an olfactory task. Interestingly, the L-trans-2,4-PDC-induced amnesia was “rescued” by memantine injected either before training or before testing, suggesting that memantine is able to restore memory recall rather than memory formation or storage (Si et al., 2004). Although the role of the glutamatergic system in the central nervous system of invertebrates is poorly understood and somewhat controversial, this result suggests a role for glutamatergic transmission in memory processing in this organism. Studies by Si et al. (2004) are consistent with the idea that memantine and MK-801-sensitive receptors in the honeybee are involved in memory recall. It is worth mentioning that other neurotransmitters, in particular acetylcholine, have also been implicated in memory processes in the honeybee (Lozano et al., 2001; Shapira et al., 2001).

Human Studies

The NMDA-receptor system in the brain has also been implicated in learning and in the process of new memory formation in humans. This has been demonstrated by several investigators using different NMDA antagonists. The NMDA-receptor antagonists ketamine and phencyclidine have been shown to evoke a range of symptoms and cognitive deficits that resemble those in schizophrenia (Honey et al., 2005; Krystal et al., 1994). Hypofunctionality of the glutamatergic system in the brain, and specifically hypofunction of the subpopulation of corticolimbic NMDA receptors, has been implicated in the pathophysiology of schizophrenia (Coyle, 1996; Olney and Farber, 1995; Tsai and Coyle, 2002). To test this hypothesis, ketamine has been used extensively for pharmacological manipulation of the NMDA receptor. Ketamine exposure leads to the blockade of NMDA receptors and consequent hypo-functionality of the glutamatergic system in the brain. The effects of the noncompetitive NMDA antagonist ketamine on cognitive function in humans have been investigated by several workers (Honey et al., 2005; Krystal et al., 1994; Lisman et al., 1998; Malhotra et al., 1996; Newcomer and Krystal, 2001; Oye et al., 1992; Rockstroh et al., 1996; Schugens et al., 1997). Overall, these studies demonstrated that NMDA-receptor blockade in humans impairs learning and memory (Honey et al., 2005; Morgan et al., 2004; Rockstroh et al., 1996). Recently, the results of an fMRI (functional magnetic resonance imaging) study showed that acute ketamine exposure altered the brain response to executive demands in a verbal working-memory task. The results of this study suggest a task-specific effect of ketamine on working memory in healthy volunteers (Honey et al., 2004). In another fMRI study using a double-blind, placebo-controlled, randomized within-subjects design, it was demonstrated that ketamine exposure disrupted frontal and hippocampal contributions to encoding and retrieval of episodic memory (Honey et al., 2005). To explore the involvement of the glutamatergic system in memory processing in human subjects, Schugens et al. (1997) investigated the effects of a single dose of a low-affinity, noncompetitive blocker of the NMDA receptors (memantine [1-1minoadamantane derivative]) on learning and memory in young, healthy volunteers. Applying a double-blind placebo-controlled design, they found no significant effects of memantine on mood, attention, or immediate and delayed verbal and visuospatial memory. However, memantine delayed the acquisition of classical eyeblink conditioning and reduced the overall frequency of conditioned responses without affecting reflex or spontaneous eyeblinks.

Administration of SDZ EAA 494, a potent enantiomerically pure NMDA antagonist (Aebischer et al., 1989), has been shown to impair the memory process in humans. SDZ EAA 494 is a competitive, highly specific antagonist at the NMDA-type excitatory amino acid receptor. To investigate the effect of this NMDA antagonist on memory and attention in humans, SDZ EAA 494 was administered either acutely or as multiple doses over a course of 1 week. The assessment included simple and complex reaction time tests to assess attention, as well as verbal, nonverbal, and spatial memory tests with immediate and late recall. Verbal and nonverbal memory performance was significantly impaired after both acute and chronic administration of SDZ EAA 494. The reaction time and spatial-memory tests were not significantly affected.

Recently, in a double-blind study, it was demonstrated that amantadine, a low-affinity NMDA-receptor channel blocker, given orally to healthy young volunteers failed to block motor learning consolidation in subjects that had already learned the task (Hadj Tahar et al., 2004). It has also been shown that ketamine given to healthy human subjects impaired learning of spatial and verbal information, but not retrieval of information learned prior to ketamine administration (Rowland et al., 2005). In another double-blind placebo-controlled design with healthy human volunteers, Morgan et al. (2004) demonstrated that ketamine treatment produced a dose-dependent impairment to episodic and working memory. Ketamine also impaired recognition memory and procedural learning.

These results support the notions that (a) NMDA receptors are involved in new memory formation in humans and, as mentioned earlier in this chapter, (b) blockade of NMDA receptors after a task has been learned has no effect on memory in humans (Hadj Tahar et al., 2004; Oye et al., 1992; Rowland et al., 2005).


Both animal and human studies clearly indicate that the NMDA-receptor system in the brain, in addition to its roles in other brain functions, is conceivably involved in the processes of learning and memory formation. This notion has been supported by consistent results from studies investigating the effects of NMDA itself, NMDA antagonists, NMDA-transporter inhibitors, and NMDA-channel blockers in transgenic mice. As an animal model of schizophrenia, NMDA-antagonist-induced memory impairment is quite useful, since working-memory impairment has been suggested to be the core cognitive deficit in schizophrenia, leading to impairment in other domains of cognition (Goldman-Rakic and Selemon, 1997; Li et al., 2003). Therefore, an animal model of working-memory impairment produced by NMDA antagonists that parallels both the NMDA hypofunctionality in specific areas of the brain (Coyle, 1996) and the cognitive deficits found in schizophrenia, including response to pharmacological treatment, would be of considerable value in studying the pathophysiology and treatment of some aspects of schizophrenia.


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