Knockout of NMDARs in CA1 and dentate gyrus fails to impair temporal control of conditioned behavior in mice.

The hippocampus has been implicated in temporal learning. Plasticity within the hippocampus requires NMDA receptor-dependent glutamatergic neurotransmission. We tested the prediction that hippocampal NMDA receptors are required for learning about time by testing mice that lack postembryonal NMDARs in the CA1 and dentate gyrus (DG) hippocampal subfields on three different appetitive temporal learning procedures. The conditional knockout mice (Grin1ΔDCA1 ) showed normal sensitivity to cue duration, responding at a higher level to a short duration cue than compared to a long duration cue. Knockout mice also showed normal precision and accuracy of response timing in the peak procedure in which reinforcement occurred after 10 s delay within a 30 s cue presentation. Mice were tested on the matching of response rates to reinforcement rates on instrumental conditioning with two levers reinforced on a concurrent variable interval schedule. Pressing on one lever was reinforced at a higher rate than the other lever. Grin1ΔDGCA1 mice showed normal sensitivity to the relative reinforcement rates of the levers. In contrast to the lack of effect of hippocampal NMDAR deletion on measures of temporal sensitivity, Grin1ΔDGCA1 mice showed increased baseline measures of magazine activity and lever pressing. Furthermore, reversal learning was enhanced when the reward contingencies were switched in the lever pressing task, but this was true only for mice trained with a large difference between relative reinforcement rates between the levers. The results failed to demonstrate a role for NMDARs in excitatory CA1 and DG neurons in learning about temporal information.

Glutamatergic dysfunction leads to a hyper-dopaminergic phenotype through deficits in short-term habituation: a mechanism for aberrant salience.

Psychosis in disorders like schizophrenia is commonly associated with aberrant salience and elevated striatal dopamine. However, the underlying cause(s) of this hyper-dopaminergic state remain elusive. Various lines of evidence point to glutamatergic dysfunction and impairments in synaptic plasticity in the etiology of schizophrenia, including deficits associated with the GluA1 AMPAR subunit. GluA1 knockout (Gria1-/-) mice provide a model of impaired synaptic plasticity in schizophrenia and exhibit a selective deficit in a form of short-term memory which underlies short-term habituation. As such, these mice are unable to reduce attention to recently presented stimuli. In this study we used fast-scan cyclic voltammetry to measure phasic dopamine responses in the nucleus accumbens of Gria1-/- mice to determine whether this behavioral phenotype might be a key driver of a hyper-dopaminergic state. There was no effect of GluA1 deletion on electrically-evoked dopamine responses in anaesthetized mice, demonstrating normal endogenous release properties of dopamine neurons in Gria1-/- mice. Furthermore, dopamine signals were initially similar in Gria1-/- mice compared to controls in response to both sucrose rewards and neutral light stimuli. They were also equally sensitive to changes in the magnitude of delivered rewards. In contrast, however, these stimulus-evoked dopamine signals failed to habituate with repeated presentations in Gria1-/- mice, resulting in a task-relevant, hyper-dopaminergic phenotype. Thus, here we show that GluA1 dysfunction, resulting in impaired short-term habituation, is a key driver of enhanced striatal dopamine responses, which may be an important contributor to aberrant salience and psychosis in psychiatric disorders like schizophrenia.

Dissociating Representations of Time and Number in Reinforcement-Rate Learning by Deletion of the GluA1 AMPA Receptor Subunit in Mice.

Theories of learning differ in whether they assume that learning reflects the strength of an association between memories or symbolic encoding of the statistical properties of events. We provide novel evidence for symbolic encoding of informational variables by demonstrating that sensitivity to time and number in learning is dissociable. Whereas responding in normal mice was dependent on reinforcement rate, responding in mice that lacked the GluA1 AMPA receptor subunit was insensitive to reinforcement rate and, instead, dependent on the number of times a cue had been paired with reinforcement. This suggests that GluA1 is necessary for weighting numeric information by temporal information in order to calculate reinforcement rate. Sample sizes per genotype varied between seven and 23 across six experiments and consisted of both male and female mice. The results provide evidence for explicit encoding of variables by animals rather than implicit encoding via variations in associative strength.

The NMDA receptor antagonist MK-801 fails to impair long-term recognition memory in mice when the state-dependency of memory is controlled.

NMDA receptor-dependent synaptic plasticity has been proposed to be important for encoding of memories. Consistent with this hypothesis, the non-competitive NMDA receptor antagonist, MK-801, has been found to impair performance on tests of memory. Interpretation of some of these findings has, however, been complicated by the fact that the drug-state of animals has differed during encoding and tests of memory. Therefore, it is possible that MK-801 may result in state-dependent retrieval or expression of memory rather than actually impairing encoding itself. We tested this hypothesis in mice using tests of object recognition memory with a 24-hour delay between the encoding and test phase. Mice received injections of either vehicle or MK-801 prior to the encoding phase and the test phase. In Experiment 1, a low dose of MK-801 (0.01 mg/kg) impaired performance when the drug-state (vehicle or MK-801) of mice changed between encoding and test, but there was no significant effect of MK-801 on encoding. In Experiment 2, a higher dose of MK-801 (0.1 mg/kg) failed to impair object recognition memory when mice received the drug prior to both encoding and test compared to mice that received vehicle. MK-801 did not affect object exploration, but it did induce locomotor hyperactivity at the higher dose. These results suggest that some previous demonstrations of MK-801 effects may reflect a failure to express or retrieve memory due to the state-dependency of memory rather than impaired encoding of memory.

Hippocampal synaptic plasticity, spatial memory and anxiety.

Recent studies using transgenic mice lacking NMDA receptors in the hippocampus challenge the long-standing hypothesis that hippocampal long-term potentiation-like mechanisms underlie the encoding and storage of associative long-term spatial memories. However, it may not be the synaptic plasticity-dependent memory hypothesis that is wrong; instead, it may be the role of the hippocampus that needs to be re-examined. We present an account of hippocampal function that explains its role in both memory and anxiety.

The group II metabotropic glutamate receptor agonist LY354740 and the D2 receptor antagonist haloperidol reduce locomotor hyperactivity but fail to rescue spatial working memory in GluA1 knockout mice.

Group II metabotropic glutamate receptor agonists have been suggested as potential anti-psychotics, at least in part, based on the observation that the agonist LY354740 appeared to rescue the cognitive deficits caused by non-competitive N-methyl-d-aspartate receptor (NMDAR) antagonists, including spatial working memory deficits in rodents. Here, we tested the ability of LY354740 to rescue spatial working memory performance in mice that lack the GluA1 subunit of the AMPA glutamate receptor, encoded by Gria1, a gene recently implicated in schizophrenia by genome-wide association studies. We found that LY354740 failed to rescue the spatial working memory deficit in Gria1-/- mice during rewarded alternation performance in the T-maze. In contrast, LY354740 did reduce the locomotor hyperactivity in these animals to a level that was similar to controls. A similar pattern was found with the dopamine receptor antagonist haloperidol, with no amelioration of the spatial working memory deficit in Gria1-/- mice, even though the same dose of haloperidol reduced their locomotor hyperactivity. These results with LY354740 contrast with the rescue of spatial working memory in models of glutamatergic hypofunction using non-competitive NMDAR antagonists. Future studies should determine whether group II mGluR agonists can rescue spatial working memory deficits with other NMDAR manipulations, including genetic models and other pharmacological manipulations of NMDAR function.

Worsening cognitive impairment and neurodegenerative pathology progressively increase risk for delirium.

BACKGROUND: Delirium is a profound neuropsychiatric disturbance precipitated by acute illness. Although dementia is the major risk factor this has typically been considered a binary quantity (i.e., cognitively impaired versus cognitively normal) with respect to delirium risk. We used humans and mice to address the hypothesis that the severity of underlying neurodegenerative changes and/or cognitive impairment progressively alters delirium risk. METHODS: Humans in a population-based longitudinal study, Vantaa 85+, were followed for incident delirium. Odds for reporting delirium at follow-up (outcome) were modeled using random-effects logistic regression, where prior cognitive impairment measured by Mini-Mental State Exam (MMSE) (exposure) was considered. To address whether underlying neurodegenerative pathology increased susceptibility to acute cognitive change, mice at three stages of neurodegenerative disease progression (ME7 model of neurodegeneration: controls, 12 weeks, and 16 weeks) were assessed for acute cognitive dysfunction upon systemic inflammation induced by bacterial lipopolysaccharide (LPS; 100 µg/kg). Synaptic and axonal correlates of susceptibility to acute dysfunction were assessed using immunohistochemistry. RESULTS: In the Vantaa cohort, 465 persons (88.4 ± 2.8 years) completed MMSE at baseline. For every MMSE point lost, risk of incident delirium increased by 5% (p = 0.02). LPS precipitated severe and fluctuating cognitive deficits in 16-week ME7 mice but lower incidence or no deficits in 12-week ME7 and controls, respectively. This was associated with progressive thalamic synaptic loss and axonal pathology. CONCLUSION: A human population-based cohort with graded severity of existing cognitive impairment and a mouse model with progressing neurodegeneration both indicate that the risk of delirium increases with greater severity of pre-existing cognitive impairment and neuropathology.

A bias-free test of human temporal bisection: Evidence against bisection at the arithmetic mean.

The temporal bisection procedure has been used to assess theories of time perception. A problem with the procedure for measuring the perceived midpoint of two durations is that the spacing of probe durations affects the length of the bisection point. Linear spacing results in longer bisection points closer to the arithmetic mean of the durations than logarithmic spacing. In three experiments, the influence of probe duration distribution was avoided by presenting a single probe duration of either the arithmetic or geometric mean of the trained durations. It was found that the number of participants that categorised the arithmetic mean as long was significantly larger than those that categorised it as short. The number of participants that categorised the geometric mean as either short or long did not significantly differ. This was true for trained durations of 0.4 s vs. 1.6 s (Experiments 1-3), 0.2 s vs. 3.2 s (Experiment 2) and 0.4 s vs. 6.4 s (Experiment 3). In Experiment 4, the probe trial distribution effect was replicated with logarithmic and linearly distributed probe durations, demonstrating that bisection occurs close to the arithmetic mean with linearly spaced probe durations. The results provide evidence against bisection at the arithmetic mean when probe spacing bias is avoided and, instead, the results are consistent with logarithmic encoding of time, or a comparison rule based on relative rather than absolute differences.

Use of Mohr diagrams to predict fracturing in rock masses, with applications for predicting sub-surface behavior.

Mohr diagrams are a simple and effective method that can help geoscientists consider, model, and predict the ranges of mechanical properties of rock, stresses, fluid pressures, and the resultant fractures that are likely to occur in the sub-surface. Mohr diagrams can be used to make predictions about how rocks may respond to change, with a transition from a stable state to fracturing occurring if there are changes in (1) the failure envelope, (2) stresses, and/or (3) fluid pressure. This article uses Mohr diagrams to address two questions of significance to the energy transition. First, how will metasedimentary rocks, which are potential geothermal reservoir rocks, respond to thermal stimulation? Second, will fractures that may influence the underground storage of radioactive waste develop in a clay sequence during exhumation? Mohr diagrams are shown to be useful for highlighting misconceptions and input data problems, leading to improved understanding of how structures develop.

The role of habituation in hippocampus-dependent spatial working memory tasks: evidence from GluA1 AMPA receptor subunit knockout mice.

Spatial alternation, win-shift behavior has been claimed to be a test of working memory in rodents that requires active maintenance of relevant, trial-specific information. In this review, we describe work with GluA1 AMPA receptor subunit knockout mice that show impaired spatial alternation, but normal spatial reference memory. Due to their selective impairment on spatial alternation, GluA1 knockout mice provide a means by which the psychological processes underlying alternation can be examined. We now argue that the spatial alternation deficit in GluA1 knockout mice is due to an inability to show stimulus-specific, short-term habituation to recently experienced stimuli. Short-term habituation involves a temporary reduction in attention paid to recently presented stimuli, and is thus a distinct process from those that are involved in working memory in humans. We have recently demonstrated that GluA1 knockout mice show impaired short-term habituation, but, surprisingly, show enhanced long-term spatial habituation. Thus, GluA1 deletion reveals that there is competition between short-term and long-term processes in memory.

Hippocampal lesions can enhance discrimination learning despite normal sensitivity to interference from incidental information.

Spatial properties of stimuli are sometimes encoded even when incidental to the demands of a particular learning task. Incidental encoding of spatial information may interfere with learning by (i) causing a failure to generalize learning between trials in which a cue is presented in different spatial locations and (ii) adding common spatial features to stimuli that predict different outcomes. Hippocampal lesions have been found to facilitate acquisition of certain tasks. This facilitation may occur because hippocampal lesions impair incidental encoding of spatial information that interferes with learning. To test this prediction mice with lesions of the hippocampus were trained on appetitive simple simultaneous discrimination tasks using inserts in the goal arms of a T-maze. It was found that hippocampal lesioned mice were facilitated at learning the discriminations, but they were sensitive to changes in spatial information in a manner that was similar to control mice. In a second experiment it was found that both control and hippocampal lesioned mice showed equivalent incidental encoding of egocentric spatial properties of the inserts, but both groups did not encode the allocentric information. These results demonstrate that mice show incidental encoding of egocentric spatial information that decreases the ability to solve simultaneous discrimination tasks. The normal egocentric spatial encoding in hippocampal lesioned mice contradicts theories of hippocampal function that suggest that the hippocampus is necessary for incidental learning per se, or is required for modulating stimulus representations based on the relevancy of information. The facilitated learning suggests that the hippocampal lesions can enhance learning of the same qualitative information as acquired by control mice.

Deletion of the GluA1 AMPA receptor subunit alters the expression of short-term memory.

Deletion of the GluA1 AMPA receptor subunit selectively impairs short-term memory for spatial locations. We further investigated this deficit by examining memory for discrete nonspatial visual stimuli in an operant chamber. Unconditioned suppression of magazine responding to visual stimuli was measured in wild-type and GluA1 knockout mice. Wild-type mice showed less suppression to a stimulus that had been presented recently than to a stimulus that had not. GluA1 knockout mice, however, showed greater suppression to a recent stimulus than to a nonrecent stimulus. Thus, GluA1 is not necessary for encoding, but affects the way that short-term memory is expressed.

Deletion of the GluA1 AMPA receptor subunit impairs recency-dependent object recognition memory.

Deletion of the GluA1 AMPA receptor subunit impairs short-term spatial recognition memory. It has been suggested that short-term recognition depends upon memory caused by the recent presentation of a stimulus that is independent of contextual-retrieval processes. The aim of the present set of experiments was to test whether the role of GluA1 extends to nonspatial recognition memory. Wild-type and GluA1 knockout mice were tested on the standard object recognition task and a context-independent recognition task that required recency-dependent memory. In a first set of experiments it was found that GluA1 deletion failed to impair performance on either of the object recognition or recency-dependent tasks. However, GluA1 knockout mice displayed increased levels of exploration of the objects in both the sample and test phases compared to controls. In contrast, when the time that GluA1 knockout mice spent exploring the objects was yoked to control mice during the sample phase, it was found that GluA1 deletion now impaired performance on both the object recognition and the recency-dependent tasks. GluA1 deletion failed to impair performance on a context-dependent recognition task regardless of whether object exposure in knockout mice was yoked to controls or not. These results demonstrate that GluA1 is necessary for nonspatial as well as spatial recognition memory and plays an important role in recency-dependent memory processes.

Reinforcement rate and the balance between excitatory and inhibitory learning: Insights from deletion of the GluA1 AMPA receptor subunit.

Conditioned responding is sensitive to reinforcement rate. This rate-sensitivity is impaired in genetically modified mice that lack the GluA1 subunit of the AMPA receptor. A time-dependent application of the Rescorla-Wagner learning rule can be used to derive an account of rate-sensitivity by reflecting the balance of excitatory and inhibitory associative strength over time. By applying this analysis, the impairment in GluA1 knockout mice may be explained by reduced sensitivity to negative prediction error and thus, impaired inhibitory learning, such that excitatory associative strength is not reduced during the nonreinforced periods of a conditioned stimulus. The article describes a test of the role of GluA1 in inhibitory learning that requires summing of the associative strengths of cues presented in compound. Mice were trained on a feature negative discrimination of the form A+/AX-. GluA1 knockout mice acquired the discrimination to a similar extent as controls. The inhibitory properties of cue X were verified in a summation test that included a control for nonassociative, external inhibition. The performance of GluA1 knockout mice was similar to that of controls. However, in line with previous findings, GluA1 deletion impaired the precision of timing of conditioned responding. These results provide further evidence that impaired sensitivity to reinforcement rate is not a consequence of impaired inhibitory learning. The results may more readily fit with accounts of rate sensitivity that propose that it reflects encoding of temporal and numeric information rather than being a consequence of changes in associative strength over time. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

Uncertainty and predictiveness modulate attention in human predictive learning.

[Correction Notice: An Erratum for this article was reported online in Journal of Experimental Psychology: General on Jan 14 2021 (see record 2021-07705-001). In the article, formatting for UK Research Councils funding was omitted. The author note and copyright line now reflect the standard acknowledgment of and formatting for the funding received for this article. All versions of this article have been corrected.] Attention determines which cues receive processing and are learned about. Learning, however, leads to attentional biases. In the study of animal learning, in some circumstances, cues that have been previously predictive of their consequences are subsequently learned about more than are nonpredictive cues, suggesting that they receive more attention. In other circumstances, cues that have previously led to uncertain consequences are learned about more than are predictive cues. In human learning, there is a clear role for predictiveness, but a role for uncertainty has been less clear. Here, in a human learning task, we show that cues that led to uncertain outcomes were subsequently learned about more than were cues that were previously predictive of their outcomes. This effect occurred when there were few uncertain cues. When the number of uncertain cues was increased, attention switched to predictive cues. This pattern of results was found for cues (1) that were uncertain because they led to 2 different outcomes equally often in a nonpredictable manner and (2) that were used in a nonlinear discrimination and were not predictive individually but were predictive in combination with other cues. This suggests that both the opposing predictiveness and uncertainty effects were determined by the relationship between individual cues and outcomes rather than the predictive strength of combined cues. These results demonstrate that learning affects attention; however, the precise nature of the effect on attention depends on the level of task complexity, which reflects a potential switch between exploration and exploitation of cues. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

The GluA1 AMPAR subunit is necessary for hedonic responding but not hedonic value in female mice.

The GluA1 subunit of the AMPA receptor has been implicated in anhedonia. Mice that lack GluA1 (Gria1 knockout mice) show reduced lick cluster size, a measure of palatability in feeding behaviour. This deficit may reflect a role for GluA1 in encoding the hedonic value of palatable substances or instead a role for GluA1 in the behavioural expression of hedonic value. We tested the role of GluA1 in hedonic value by assessing sensitivity to changes in the rewarding property of sucrose as a consequence of negative/positive contrast effects in female mice. During training, on half of the days consumption of a flavour (CS+) mixed with 4% sucrose was preceded by consumption of 1% sucrose (positive contrast). On the other half of days consumption of a different flavour (CS-) mixed with 4% sucrose was preceded by consumption of 16% sucrose (negative contrast). In the test session both wild-type, controls and Gria1 knockout mice consumed more of the CS+ flavour than the CS- flavour. While Gria1 knockout mice showed reduced lick cluster sizes, both genotypes made larger lick clusters for the CS+ flavour than the CS- flavour suggesting that the CS+ was more palatable than the CS-. A follow up experiment in normal mice demonstrated that the negative contrast procedure resulted in a conditioned reduction of palatability of the CS- in comparison to an associatively neutral, novel flavour. The results failed to demonstrate a role for GluA1 in hedonic value suggesting that, instead, GluA1 is necessary for hedonic responding.

Enhanced long-term and impaired short-term spatial memory in GluA1 AMPA receptor subunit knockout mice: evidence for a dual-process memory model.

The GluA1 AMPA receptor subunit is a key mediator of hippocampal synaptic plasticity and is especially important for a rapidly-induced, short-lasting form of potentiation. GluA1 gene deletion impairs hippocampus-dependent, spatial working memory, but spares hippocampus-dependent spatial reference memory. These findings may reflect the necessity of GluA1-dependent synaptic plasticity for short-term memory of recently visited places, but not for the ability to form long-term associations between a particular spatial location and an outcome. This hypothesis is in concordance with the theory that short-term and long-term memory depend on dissociable psychological processes. In this study we tested GluA1-/- mice on both short-term and long-term spatial memory using a simple novelty preference task. Mice were given a series of repeated exposures to a particular spatial location (the arm of a Y-maze) before their preference for a novel spatial location (the unvisited arm of the maze) over the familiar spatial location was assessed. GluA1-/- mice were impaired if the interval between the trials was short (1 min), but showed enhanced spatial memory if the interval between the trials was long (24 h). This enhancement was caused by the interval between the exposure trials rather than the interval prior to the test, thus demonstrating enhanced learning and not simply enhanced performance or expression of memory. This seemingly paradoxical enhancement of hippocampus-dependent spatial learning may be caused by GluA1 gene deletion reducing the detrimental effects of short-term memory on subsequent long-term learning. Thus, these results support a dual-process model of memory in which short-term and long-term memory are separate and sometimes competitive processes.

Cue duration determines response rate but not rate of acquisition of Pavlovian conditioning in mice.

The duration of a conditioned stimulus (CS) is a key determinant of Pavlovian conditioning. Rate estimation theory (RET) proposes that reinforcement rate is calculated over cumulative exposure to a cue and the reinforcement rate of a cue, relative to the background reinforcement rate, determines the speed of acquisition of conditioned responding. Consequently, RET predicts that shorter-duration cues require fewer trials to acquisition than longer-duration cues due to the difference in reinforcement rates. We tested this prediction by reanalysing the results of a previously published experiment. Mice received appetitive Pavlovian conditioning of magazine approach behaviour with a 10-s CS and a 40-s CS. Cue duration did not affect the rate at which responding emerged or the rate at which it peaked. The 10-s CS did elicit higher levels of responding than the 40-s CS. These results are not consistent with rate estimation theory. Instead, they are consistent with an associative analysis that assumes that asymptotic levels of responding reflect the balance between increments and decrements in associative strength across cumulative exposure to a cue.

Spontaneous object-location memory based on environmental geometry is impaired by both hippocampal and dorsolateral striatal lesions.

We examined the role of the hippocampus and the dorsolateral striatum in the representation of environmental geometry using a spontaneous object recognition procedure. Rats were placed in a kite-shaped arena and allowed to explore two distinctive objects in each of the right-angled corners. In a different room, rats were then placed into a rectangular arena with two identical copies of one of the two objects from the exploration phase, one in each of the two adjacent right-angled corners that were separated by a long wall. Time spent exploring these two objects was recorded as a measure of recognition memory. Since both objects were in different locations with respect to the room (different between exploration and test phases) and the global geometry (also different between exploration and test phases), differential exploration of the objects must be a result of initial habituation to the object relative to its local geometric context. The results indicated an impairment in processing the local geometric features of the environment for both hippocampus and dorsolateral striatum lesioned rats compared with sham-operated controls, though a control experiment showed these rats were unimpaired in a standard object recognition task. The dorsolateral striatum has previously been implicated in egocentric route-learning, but the results indicate an unexpected role for the dorsolateral striatum in processing the spatial layout of the environment. The results provide the first evidence that lesions to the hippocampus and dorsolateral striatum impair spontaneous encoding of local environmental geometric features.

NMDA receptor subunit NR2A is required for rapidly acquired spatial working memory but not incremental spatial reference memory.

NMDA receptors (NMDARs) containing NR2A (epsilon1) subunits are key contributors to hippocampal long-term potentiation (LTP) induction in adult animals and have therefore been widely implicated in hippocampus-dependent spatial learning. Here we show that mice lacking the NR2A subunit or its C-terminal intracellular domain exhibit impaired spatial working memory (SWM) but normal spatial reference memory (SRM). Both NR2A mutants acquired the SRM version of the water maze task, and the SRM component of the radial maze, as well as controls. They were, however, impaired on a non-matching-to-place T-maze task, and on the SWM component of the radial maze. In addition, NR2A knock-out mice displayed a diminished spatial novelty preference in a spontaneous exploration Y-maze task, and were impaired on a T-maze task in which distinctive inserts present on the floor of the maze determined which goal arm contained the reward, but only if there was a discontiguity between the conditional cue and the place at which the reward was delivered. This dissociation of spatial memory into distinctive components is strikingly similar to results obtained with mice lacking glutamate receptor-A (GluR-A)-containing AMPA receptors, which support long-term potentiation expression. These results identify a specific role for a NMDAR-dependent signaling pathway that leads to the activation of a GluR-A-dependent expression mechanism in a rapidly acquired, flexible form of spatial memory. This mechanism depends on the C-terminal intracellular domain of the NR2A subunit. In contrast, the ability to associate a particular spatial location with the water maze escape platform or food reward is NR2A independent, as well as GluR-A independent.