N-methyl-D-aspartate antagonists and working memory performance: comparison with the effects of scopolamine, propranolol, diazepam, and phenylisopropyladenosine.

The effects of the competitive N-methyl-D-aspartate (NMDA) antagonists CPP (5 & 10 mg/kg) and NPC 12626 (25 & 40 mg/kg) and the noncompetitive NMDA antagonists phencyclidine (1, 3, & 6.25 mg/kg) and MK 801 (0.1 & 0.2 mg/kg) on performance of rats on a nonspatial delayed matching-to-sample working memory task were evaluated. At the highest dose, each NMDA antagonist reduced choice accuracy at all retention intervals. In contrast, the reference anticholinergic agent scopolamine selectively reduced accuracy at long retention intervals, suggesting that scopolamine but not the NMDA antagonists directly interfered with time-dependent working memory retention. Propranolol, diazepam, and phenylisopropyladenosine had little or no effect on choice accuracy, suggesting that noradrenergic, gamma-aminobutyric acid-diazepam, and adenosine receptors may be relatively unimportant for working memory performance as assessed in this task. The NMDA antagonists also differed from scopolamine in that doses of NMDA antagonists that reduced response accuracy also reduced response probability, altered bias (competitive antagonists only), and increased intertrial interval responding (noncompetitive antagonists only). It was concluded that NMDA antagonists disrupt cognitive functions including, but not limited to, those required for accurate working memory performance.     

Impact of postnatal blockade of N-methyl-D-aspartate receptors on rat behavior: a search for a new developmental model of schizophrenia

The malfunction of glutamatergic neurotransmission in the neonatal or postnatal periods may be a risk factor for the appearance of neuroanatomical, neurochemical or functional changes that are characteristic of schizophrenia. Thus, the present study was undertaken to investigate whether blockade of N-methyl-d-aspartate (NMDA) receptors in the postnatal period influences rat behavior in tests characterizing schizophrenia-like deficits such as psychomotor agitation, impairments of sensorimotor gating, working memory, and intensity of social interactions. (E)-2-amino-4-methyl-5-phosphono-3-pentenoic acid (CGP 40116), a competitive antagonist of NMDA receptors, was given postnatally (1.25 mg/kg on days 1, 3, 6, 9; 2.5 mg/kg on days 12, 15, 18; and finally 5 mg/kg on day 21, all injections s.c.), and rats were tested at 60 days old. We found that blockade of NMDA receptors in the postnatal period led to an enhancement of exploration, mimicking psychomotor agitation, impairments in sensorimotor gating as measured by a prepulse-evoked inhibition of acoustic startle response, and an impaired working memory, as measured by an increase in the latency to achieve accurate rate of response in the delayed alternation task. Decreases in non-aggressive social interactions and increases in aggressive interactions were also observed. In addition to cognitive deficits typical of schizophrenia, rats treated postnatally with NMDA receptor antagonists also showed higher level of fear exhibited in the elevated plus maze. Thus, the blockade of NMDA receptors in the postnatal period may model deficits that are characteristic of schizophrenia.     

Effects of AP5 infusion into the lateral ventricle on the activities and hippocampal electrical patterns of sleep episodes in rats

Although N-methyl-D-aspartate (NMDA) receptors of the hippocampus are mainly associated with learning and memory that might occur "on-line" during sharp waves (SPWs) and theta-rhythm, the participation of hippocampal NMDA receptors in sleep-related processes has not been well studied. In this study, the activity of sleep episodes, hippocampal SPWs and theta-rhythm were recorded in rats received a repeated infusion of NMDA receptor antagonist, D,L-2-amino-5-phosphonopentanoic acid (AP5), into the lateral ventricle in a 5-h daytime sleep. The first trial AP5 infusion (30 mM/2 microl) did not change measures of the activity of slow wave sleep (SWS), paradoxical sleep (PS) and awake episodes, but induced a delay in the latency of the first onset of PS; in the hippocampal EEG, it increased the amplitude of SPWs within SWS and shifted the amplitude/spectral power of theta-rhythm from high to low frequency within PS. The repeated AP5 infusion augmented the activity of SWS, and impaired PS and awake episodes; in the EEG-sleep picture, it maintained high scores of SPWs with the complete blockade of theta-rhythm generation. When AP5 rat was woken, the theta-rhythm was seen during exploratory behavior. These findings provide evidence that hippocampal NMDA receptors via SPWs or directly associated with the synaptic events of theta-rhythm generation are critical for the PS activities.     

Application of a novel Active Allothetic Place Avoidance task (AAPA) in testing a pharmacological model of psychosis in rats: comparison with the Morris Water Maze

Administration of a non-competitive NMDA antagonist dizocilpine (MK-801) was proposed to be an animal model of psychosis. NMDA-receptor blockade is accompanied by increased locomotion, behavioral deficits, and other changes resembling psychotic symptoms. However, the role of NMDA-receptors in organizing brain representations is not understood yet. We tested the effect of NMDA-receptor blockade by systemic administration of dizocilpine at two different doses (0.1 or 0.2 mg/kg) in a recently designed Active Allothetic Place Avoidance (AAPA), a task which requires rats to separate spatial stimuli from two continuously dissociated subsets. The effect of dizocilpine on learning in the AAPA task was compared with its effect on acquisition of the reference memory version of the Morris Water Maze task. Both doses impaired performance in the Morris Water Maze task, whereas only the higher dose impaired performance in the AAPA task. The Morris Water Maze appears to be more sensitive to dizocilpine-induced behavioral deficit than the AAPA task. These findings support the notion that these two tasks are differentially dependent on the NMDA-receptor function.     

Association of sleep parameters and memory in intact old rats and young rats with lesions in the nucleus basalis magnocellularis

Relations between sleep and memory were examined as a function of aging in rats. Sleep (24 hr), passive avoidance retention, and choline acetyltransferase (CAT) activity were assessed in 3 age-groups (6, 15, and 24 months old). Age-related alterations were evident in sleep, memory, and cortical and striatal CAT activity. Retention deficits in old rats were significantly correlated with several measures of paradoxical sleep. Similar analyses in 6- and 15-month-old rats with ibotenic acid-induced lesions of the nucleus basalis magnocellularis (NBM) showed several alterations in sleep, memory, and cortical CAT activity comparable to those seen in the old rats. One measure of paradoxical sleep, bout duration, correlated significantly with retention scores in rats with lesions. Thus, fragmented paradoxical sleep accompanies memory impairments in old rats and in young rats with NBM lesions.     

The effects of dopaminergic agonists on genital reflexes in paradoxical sleep-deprived male rats

Dopamine (DA) agonists provide evidence that different receptor subtypes in the central nervous system (CNS) have influence in sexual behavior. Sleep deprivation induces supersensibility of DA receptors and previous work has shown that the DA agonist apomorphine enhances spontaneous genital reflexes (penile erection-PE and ejaculation-EJ) in rats deprived of paradoxical sleep. The present study sought to extend the latter finding by assessing the effects of other DA agonists in paradoxical sleep-deprived (PSD) male rats. The DA drugs (bromocriptine and piribedil) were acutely administered to rats that had been deprived of sleep for 4 days and to normal controls. Sleep deprivation alone induced PE and this effect was potentiated by piribedil, with maximal effects occurring with the 8 mg/kg dose, whereas only one dose of bromocriptine (8 mg/kg) induced more PE in PSD rats than in non-deprived treated controls. EJs were increased in piribedil PSD groups but this response was absent after bromocriptine treatment in the dose range tested. Our data show the genital reflexes that occurred in PSD rats are potentialized by piribedil and not by bromocriptine. These DA agonists showed distinct effects in sexual response suggesting that these effects are probably due to PSD-induced DA receptor supersensitivity even though different mechanisms are involved.     

Sleep and memory relationships in intact old and amnestic young rats

Age-related changes in sleep are observed in many species, including rats and humans. Old rats often exhibit less total and paradoxical sleep, shorter sleep bouts and more random sleep-wake periods across 24 hours, than young rats. This paper evaluates recent evidence that deterioration of selected sleep parameters, usually involving levels of paradoxical sleep or durations of sleep bouts, may be related to deterioration of memory in old rats. Similar findings are reviewed with respect to young animals with different forms of experimentally-induced amnesia. Furthermore, a drug that enhances memory in rats and old humans, glucose, also enhances paradoxical sleep in old rats. These data suggest the utility of sleep measures as neurobiological markers of memory dysfunction in old rats.     

Two phases of behavioral plasticity in rats following unilateral excitotoxic lesion of the hippocampus.

We investigated the effects of dizocilpine, a non-competitive N-methyl-D-aspartate receptor antagonist, on spatial reference and working memory in a radial arm maze task in rats with a unilateral hippocampal lesion. At a dose of 0.2 mg/kg to intact rats, dizocilpine significantly impaired both reference and working memory, and produced ataxia and impairment of food intake; at 0.1 mg/kg, dizocilpine had no effect on performance. Unilateral hippocampal lesion induced by quinolinic acid produced a marked working memory deficit concomitant with a slight but significant impairment of reference memory when mnemonic ability was examined one week after the lesion. The spatial memory deficits in the rats with a unilateral hippocampal lesion were ameliorated by repeated daily trainings over a 21-day period. Following recovery of the spatial memory deficits produced by the brain lesion (four weeks after the brain lesion), dizocilpine (0.1 mg/kg) significantly impaired both reference and working memory, without affecting general behavior or food intake in the brain-lesioned rats. An impairment of working memory, but not reference memory, by dizocilpine was observed six weeks after the brain lesion. However, the disrupting effect of dizocilpine at 0.1 mg/kg on spatial working memory had disappeared at eight weeks after the lesion. Ten weeks after the brain lesion, dizocilpine at 0.2 mg/kg was necessary to induce spatial memory impairment, which was accompanied by motor and food intake deficits, as in intact rats. In sham-operated rats, the dose-response effects of dizocilpine did not differ from those in intact rats at any time after the operation. These results suggest that two phases of behavioral plasticity take place, depending on demand, to compensate for brain dysfunction after the unilateral lesion of the hippocampus in rats.     

Water T-maze,an improved method to assess spatial working memory in rats: Pharmacological validation

The present study was performed to validate a spatial working memory task using pharmacological manipulations. The water escape T-maze combines the advantages of the Morris water maze and the T-maze while minimizing the disadvantages. Scopolamine (1 mg/kg), a drug that affects cognitive function in spatial working memory tasks, significantly decreased the rats’ performance in the present delayed alternation task. Glutamate neurotransmission plays an important role in the maintenance of working memory; rats treated with dizocilpine (MK-801; 0.125–0.25 mg/kg), a N-methyl-d-aspartate (NMDA) receptor antagonist, were impaired in this task. In agreement with evidence showing a functional interaction between ionotropic and metabotropic glutamatergic receptors, 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a mGlu₅ receptor antagonist, at a dose (1 mg/kg) which by itself had no significant effects, enhanced MK-801-induced impairments of spatial working memory. These evidences suggest that the water escape T-maze might be a valid method to assess spatial working memory, sensitive to pharmacological manipulations.     

Effects of Memantine on Convulsive Reactions and the Organization of Sleep in Krushinskii–Molodkina Rats with an Inherited Predisposition to Audiogenic Convulsions

Krushinskii–Molodkina rats, which have a genetic predisposition to audiogenic convulsions, are used as a natural animal model for studies of the actions of anticonvulsants. It is important to understand the extent to which changes in glutamatergic synaptic transmission is involved in the mechanisms producing convulsive states and in the functional organization of the sleep–waking cycle in rats of this strain. The present report describes experiments addressing this, in which i.m. doses of 5 and 10 mg/kg of a noncompetitive NMDA glutamate receptor antagonist of the memantine type were given at different times (30 min, 1, 2, and 3 h) before presentation of sound stimuli (sine-wave tones at 8 kHz, 90 dB). Effects on the latent periods of the initial motor excitation, the appearance of clonic convulsions of different intensities, and, finally, tonic convulsions with limb and tail extension were evaluated. The greatest attenuation of convulsive seizures, to a level consisting only of motor excitation, was obtained in 60% of the rats between 1 and 2 h after administration. There were no differences between the effects of doses of 5 and 10 mg/kg. When doses were given 3 h before sound provocation, convulsive reactions became more marked than at 2 h, though they were nevertheless more marked than in controls. Krushinskii–Molodkina rats with chronically implanted electrodes for recording brain electrical activity were used to study the effects of memantine on the organization of sleep. These experiments showed that the rats’ sleep during the first hour after dosage consisted only of short episodes of superficial slow-wave sleep, and that even this sleep disappeared completely 54.4 ± 4.9 and 39.9 ± 5.2 min after administration of the agent at doses of 5 and 7 mg/kg, respectively. Rats showed a complete absence of sleep for 2 and 2.5 h, respectively, after which episodes of slow-wave sleep reappeared. The first episodes of REM sleep was seen in rats only after 3.3 ± 0.2 and 3.7 ± 0.2 h after memantine injections. The appearance of these episodes provided evidence that the effects of memantine on the activity of the somnogenic system of the animals’ brains were complete and that recovery of the normal organization of the sleep–waking cycle had started. The synchronicity and codirectionality of the blocking action of memantine on sleep organization and measures of audiogenic convulsions in Krushinskii–Molodkina rats is evidence for the involvement of glutamatergic synapses with NMDA receptors in both the regulation of the somnogenic systems and the pathogenesis of epileptiform manifestations in rats.     

Memantine reduces oxidative damage and enhances long-term recognition memory in aged rats

Many neurodegenerative diseases, including Alzheimer's (AD), Parkinson's (PD) and Huntington's diseases (HD), are caused by different mechanisms but may share a common pathway to neuronal injury as a result of the overstimulation of glutamate receptors. It has been suggested that this pathway can be involved in generation of cognitive deficits associated with normal aging. Previous studies performed in our laboratory have demonstrated that aged rats presented recognition memory deficits. The aim of the present study was to evaluate the effect of memantine, a low-affinity N-methyl-D-aspartate (NMDA) receptor antagonist, on age-induced recognition memory deficits. Additionally, parameters of oxidative damage in cerebral regions related to memory formation were evaluated. In order to do that, male Wistar rats (24 months old) received daily injections of saline solution or memantine (20 mg/kg i.p.) during 21 days. The animals were submitted to a novel object recognition task 1 week after the last injection. Memantine-treated rats showed normal recognition memory while the saline group showed long-term recognition memory deficits. The results show that memantine is able to reverse age-induced recognition memory deficits. We also demonstrated that memantine reduced the oxidative damage to proteins in cortex and hippocampus, two important brain regions involved in memory formation. Thus, the present findings suggest that, at least in part, age-induced cognitive deficits are related to oxidative damage promoted by NMDA receptor overactivation.     

Differential role of N-methyl-d-aspartate receptor subunits 2A and 2B in mediating phencyclidine-induced perinatal neuronal apoptosis and behavioral deficits

The mechanism underlying phencyclidine (PCP)-induced apoptosis in perinatal rats and the development of schizophrenia-like behaviors is incompletely understood. We used antagonists for N-methyl-d-aspartate (NMDA) receptor subunit NR2A- and NR2B-containing NMDA receptor to test the hypothesis that the behavioral and apoptotic effects of PCP are mediated by blockade of NR1/NR2A-containing receptors, rather than NR1/NR2B-containing receptors. Sprague-Dawley rats were treated on PN7, PN9, and PN11 with PCP (10 mg/kg), PEAQX (NR2A-preferring antagonist; 10, 20, or 40 mg/kg), or ifenprodil (selective NR2B antagonist; 1, 5, or 10 mg/kg) and sacrificed for measurement of caspase-3 activity (an index of apoptosis) or allowed to age and tested for locomotor sensitization to PCP challenge on PN28-PN35. PCP or PEAQX on PN7, PN9, and PN11 markedly elevated caspase-3 activity in the cortex; ifenprodil showed no effect. Striatal apoptosis was evident only after subchronic treatment with a high dose of PEAQX (20 mg/kg). Animals treated with PCP or PEAQX on PN7, PN9, and PN11 showed a sensitized locomotor response to PCP challenge on PN28-PN35. Ifenprodil treatment had no effect on either measure. Therefore, PCP blockade of cortical NR1/NR2A, rather than NR1/NR2B, appears to be responsible for PCP-induced apoptosis and the development of long-lasting behavioral deficits.     

Effect of prolonged administration of nitrazepam on sleep cycles in rats

The effect of nitrazepam given as a single dose or by prolonged intraperitoneal injection, on sleep cycles in male Wistar rats was studied. In a dose of 1 mg/kg nitrazepam had no significant effect on sleep cycles whether given as a single or by prolonged injection. In a dose of 10 mg/kg a single injection of nitrazepam reduced the duration of paradoxical sleep and the number of sleep cycles during 5 h of recording, whereas prolonged (7–14 days) administration of the drug led to an increase in these indices. Withholding the drug after its prolonged administration was followed by a further increase in the number of sleep cycles and the duration of paradoxical sleep. No correlation was found between the hypnotic and muscle-relaxing action of nitrazepam during its prolonged administration.Institute of Pharmacology, Academy of Medical Sciences of the USSR, Moscow. Institute of Pharmacology, Czechoslovak Academy of Sciences, Prague. (Presented by Academician of the Academy of Medical Sciences of the USSR V. V. Zakusov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 81, No. 2, pp. 188–190, February, 1976.     

Tetrahydroaminoacridine alleviates medial septal lesion-induced and age-related spatial reference but not working memory deficits

This study examined the effects of tetrahydroaminoacridine (THA, an anticholinesterase) on water-maze (WM) spatial reference (stable platform location during training) and spatial working memory (reversal of platform location) learning in young intact/medial septal (MS)-lesioned and aged rats. THA (1 or 3 mg/kg, IP) had no effect on reference or working memory performance of young intact rats. MS lesions decreased cholineacetyltransferase activity in the hippocampus and also impaired spatial reference and working memory. THA at 3 mg/kg stabilized MS lesion-induced reference memory performance deficit (path length increase), but was ineffective at 1 mg/kg. THA had no effect on the working memory performance of MS-lesioned rats. Aged rats were impaired in spatial reference and working memory tasks. THA at 3 mg/kg partially stabilized the age-induced spatial reference memory deficits, but was ineffective at 1 mg/kg. THA at either 1 or 3 mg/kg did not alleviate the age-related deficit in the working memory version of WM. The present results suggest that some of the age-related WM deficits may be related to the degeneration of the MS-hippocampus cholinergic system and that THA may be effective in stabilizing the reference memory deficits induced by hippocampal cholinergic dysfunction.     

Differentiations of the effect of NMDA on the spatial learning of rats with 4 and 12 week diabetes mellitus

This study examines possible interactions between behavioral effects and influence of N-methyl-D-aspartate acid (NMDA) receptors in 4 and 12-week streptozotocin (STZ) induced diabetic rats. Effects of NMDA receptor agonist on spatial learning were tested in control groups of rats and in rats with 4 and 12 weeks diabetes mellitus (DM). Experimental diabetes was induced by a single intravenous injection of streptozotocin at a dose of 65 m/kg, dissolved in citrate buffer. We used the water maze task and examined the acquisition and the retrieval of spatial memory in rats. In our present experiments, we observed that DM had no significant influence on acquisition and retrieval in 4 week diabetic rats on Morris water maze, but impaired examined parameters in 12 week diabetic rats in this test. The NMDA receptor agonist did not influence acquisition but increased recall on water maze in 12 week streptozotocin diabetic rats.     

Lack of task specificity and absence of posttraining effects of atropine on learning

Three experiments are reported whose purpose was to examine the effect of the cholinergic antagonist atropine on the acquisition of different learning tasks known to be sensitive or insensitive to impairment by hippocampal lesions; on the retention of performance acquired in the absence of the drug; and on memory consolidation immediately after daily training trials. In Experiment 1, atropine sulfate (10 or 50 mg/kg, ip), injected 30 min prior to training, severely impaired learning of both spatial and nonspatial discrimination tasks when compared with saline or atropine methylnitrate (50 mg/kg). In Experiment 2, atropine sulfate (50 mg/kg) also impaired spatial discrimination accuracy in rats previously trained to asymptote under drug-free conditions. These deficits were not due to either peripheral drug effects or gross sensorimotor impairments. In Experiment 3, daily posttraining injections of atropine sulfate (50 mg/kg) failed to influence either learning or subsequent retention of place navigation in rats that were trained to find a single hidden escape platform. The data confirm that profound learning deficits occur when training is conducted under atropine but offer no support to the hypothesis that cholinergic neurons play an important role in memory consolidation or other posttraining processes. Furthermore, these results point to dissimilarities between the behavioral impairments induced by cholinergic blockade and hippocampal lesions under appropriate test regimes.     

Effects of combined acetylcholinesterase inhibition and serotonergic receptor blockade on age-associated memory impairments in rats

We recently reported that post-training administration of serotonergic receptor antagonists attenuated the inhibitory-avoidance memory deficits normally exhibited by aged rats. In the present study, we determined whether a subeffective dose of the serotonergic type-2 receptor antagonist, ketanserin, would augment the facilitative effects produced by the acetylcholinesterase inhibitor, physostigmine, on memory in aged rats using the same task. The drugs were injected intraperitoneally alone, or in combination, immediately following training. Retention testing occurred 24 hours following training. A dose-dependent enhancement of memory was demonstrated as a result of the two treatment conditions (physostigmine 0.01–10.0 μ/kg, ketanserin 1.0 mg/kg + physostigmine 0.001–0.01 μ/kg). The facilitation of memory produced by the combined treatment was observed at doses well below those required to produce a similar effect when each drug was administered alone. The results provide additional evidence for an interaction between the cholinergic and serotonergic neurotransmitter systems in learning and memory, and may have important implications in the treatment of age-related memory impairments.     

N-methyl-D-aspartate receptors in the medial septal area have a role in spatial and emotional learning in the rat

Cholinergic and GABAergic neurons in the medial septal/vertical limb of the diagonal band of Broca (MS/vDB) area project to the hippocampus and constitute the septohippocampal pathway, which has been implicated in learning and memory. There is also evidence for extrinsic and intrinsic glutamatergic neurons in the MS/vDB, which by regulating septohippocampal neurons can influence hippocampal functions. The potential role of glutamatergic N-methyl-D-aspartate (NMDA) receptors within the MS/vDB for spatial and emotional learning was studied using the water maze and step-through passive avoidance (PA) tasks, which are both hippocampal-dependent. Blockade of septal NMDA receptors by infusion of the competitive NMDA receptor antagonist D-(-)-2-amino-5-phosphonopentanoic acid (D-AP5) (0.3-5 microg/rat), infused 15 min prior to training, impaired spatial learning and memory at the 5 microg dose of D-AP5, while doses of 0.3 and 1 microg per rat had no effect. The impairment in spatial learning appears not to be caused by sensorimotor or motivational disturbances, or anxiogenic-like behavior. Thus, d-AP5-treated rats were not impaired in swim performance or visuospatial abilities and spent more time in the open arms of the elevated plus-maze. In the PA task, intraseptal D-AP5 infused 15 min before training impaired retention as examined 24 h after training. This impairment was observed already at the 0.3 microg dose, suggesting that NMDA receptors within the MS/vDB may be more important for emotional than spatial memory. In summary, the present data indicate that changes in septal glutamate transmission and NMDA receptor activity can influence activity-dependent synaptic plasticity in the hippocampus and thereby learning and memory.     

Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability

The authors examined set-shifting abilities in rats injected with antagonists of N-methyl-D-aspartate (NMDA) receptors (MK801) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptors (LY293558) into the medial prefrontal cortex (mPFC). Set-shifting was assessed with a maze-based task requiring a switch between brightness and texture discrimination strategies. Intra-mPFC injection of MK801 prior to training on the 2nd discrimination impaired discrimination strategy acquisition. The MK801-induced deficit was due to increased perseverative responding. AMPA receptor blockade also impaired acquisition of the 2nd discrimination; these impairments were due to more general cognitive deficits. Results suggest that, within the mPFC, both AMPA and NMDA receptors are necessary for set-shifting, and that NMDA receptor hypofunction impairs the capacity to modify existing knowledge or to inhibit responses that are no longer appropriate.     

Sleep deprivation-induced alterations in excitatory synaptic transmission in the CA1 region of the rat hippocampus

Although the function of sleep remains elusive, there is compelling evidence to suggest that sleep plays an important role in learning and memory. A number of studies have now shown that sleep deprivation (SD) results in significant impairment of long-term potentiation (LTP) in the hippocampus. In this study, we have attempted to determine the mechanisms responsible for this impairment. After 72 h SD using the multiple-platform technique, we observed a reduction in the whole-cell recorded NMDA/AMPA ratio of CA1 pyramidal cells in response to Schaffer collateral stimulation. This impairment was specific to sleep deprivation as rats placed over a single large platform, which allowed sleep, had a normal NMDA/AMPA ratio. mEPSCs evoked by local application of a high osmolarity solution revealed no differences in the AMPA receptor function. NMDA currents recorded from outside-out patches excised from the distal dendrites of CA1 cells displayed a reduction in amplitude after SD. While there were no alterations in the glutamate sensitivity, channel open probability or the single channel conductance of the receptor, a crosslinking assay demonstrated that the NR1 and NR2A subunits of NMDA receptors were preferentially retained in the cytoplasm after SD, indicating that SD alters NMDAR surface expression. In summary, we have identified a potential mechanism underlying SD-induced LTP impairment. This synaptic alteration may underlie the cognitive deficits seen following sleep deprivation and could represent a target for future intervention studies.