Pruning of dendrites and restoration of function after brain damage: Role of the NMDA receptor

Following unilateral injury to the forelimb-representation area of the sensorimotor cortex (FL-SMC) in adult rats, there occurs a biphasic process of overgrowth and partial elimination of neuronal dendrites in layer V pyramidal cells of the homotopic cortex of the opposite hemisphere. These neural events are associated with hyper-reliance on the non-impaired forelimb for postural-supporting and related movements that compensate for impaired function in the other forelimb. The overgrowth appears to be use-dependent because it can be prevented by one-sleeve casts that restrict the range of movements of the unimpaired limb during the period of expected neural growth. In development, "exuberant" growth of neurons is often followed by pruning, a process that has been associated with activity-dependency and a glutamatergic N-methyl-D-aspartate (NMDA) mechanism. To determine whether a related mechanism might be operating in adult animals recovering from brain damage, MK-801, a non-competitive NMDA receptor antagonist, was administered during the pruning phase in adult rats that had sustained FL-SMC lesions. MK-801 prevented the elimination of dendrites in the FL-SMC rats and had no effect on dendritic arborization in Sham-operated rats. MK-801 reinstated dysfunction in the previously-recovered forelimb in FL-SMC rats, and had no effect in Sham-operated rats. These data are consistent with the possibility that there may be a functionally important pruning mechanism with a glutamatergic component in adults with FL-SMC lesions, just as in the developing brain.     

MK801 prevents quinolinic acid-induced behavioral deficits and neurotoxicity in the striatum

Bilateral intrastriatal injections of quinolinic acid (QA) (180 nmoles) induced weight loss and neurologic and behavioral deficits including convulsions, decreased catalepsy response to haloperidol, increased nocturnal locomotor activity, and abnormal feeding behavior in adult male Sprague-Dawley rats. Pretreatment with the noncompetitive N-methyl-D-aspartate (NMDA) antagonist, MK801 (4 mg/kg IP) 30 min prior to stereotaxic surgery prevented the appearance of all QA-induced behavioral abnormalities and prevented weight loss. Twelve weeks after surgery the QA-lesioned animals recovered to sham levels on feeding behavior and nocturnal locomotor activity, but showed persistent reductions in haloperidol-induced catalepsy. Histological examination of the QA-lesioned brains showed extensive lesions of the dorsolateral striatum and frontoparietal cortex. MK801 pretreatment protected against these lesions. These results confirm that MK801 treatment prevents the appearance of neuropathological damage after QA neurotoxicity, and further show that neuronal protection with MK801 is correlated with the absence of QA-induced behavioral deficits.     

Psychosis: pathological activation of limbic thalamocortical circuits by psychomimetics and schizophrenia?

Non-competitive NMDA receptor antagonists, such as phencyclidine, ketamine and MK801, produce psychosis in humans. These drugs also produce injury to cingulate-retrosplenial cortex in adult rodents that can be prevented by GABA-receptor agonists and antipsychotics such as haloperidol and clozapine. MK801 injections into anterior thalamus reproduce limbic cortex injury, and GABA-receptor agonist injections into anterior thalamus prevent injury produced by systemic MK801. Inhibition of NMDA receptors on GABAergic thalamic reticular nucleus neurons might activate thalamocortical 'injury' circuits in animals. Pathological activation of thalamocortical circuits might also mediate the psychosis produced by NMDA-receptor antagonists in humans, and might contribute to psychosis in schizophrenia.     

Post-lesion administration of the NMDA receptor antagonist MK-801 does not impair motor recovery after unilateral sensorimotor cortex injury in the rat

Although treatment with N-methyl-D-aspartate (NMDA) receptor antagonists reduce neuronal loss after cerebral infarction and brain trauma in laboratory animals, there is little data concerning the effects of these drugs on behavioral recovery. Because NMDA receptor antagonists impede certain kinds of learning, and because motor recovery after sensorimotor cortex injury in the rat is dependent on post-lesion experience, we hypothesized that treatment with MK-801 after focal brain injury would be detrimental. Groups of rats were first trained to traverse a narrow elevated beam and then subjected a right sensorimotor cortex suction-ablation lesion. In the first experiment, 24 h later, each rat received a single dose of either saline or the NMDA receptor antagonist MK-801 (0.5, 1.0, or 2.0 mg/kg). Beam-walking recovery was measured over the next 12 days. In a second experiment, rats were given 3 doses of MK-801 (0.5 mg/kg) at 24 h intervals beginning 24 h after cortex injury. In a third experiment, lesioned and sham-operated rats were allowed to recover for 12 days and then given MK-801 (0.5 mg/kg). Despite obvious behavioral effects of the drug, there was no overall difference in beam-walking performances among the treatment groups in any of the experiments. If 're-learning' is involved in motor recovery after cortex injury, the present results suggest that the process is not susceptible to permanent disruption by the early or late administration of an NMDA receptor antagonist.     

Delayed onset of enhanced MK-801-induced motor hyperactivity after neonatal lesions of the rat ventral hippocampus.

BACKGROUND: Abnormalities in the glutamatergic system, glutamate/dopamine/gamma-aminobutyric acid interactions, and cortical development are implicated in schizophrenia. Moreover, patients with schizophrenia show symptom exacerbation in response to N-methyl-D-aspartate (NMDA) antagonist drugs. Using an animal model of schizophrenia, we compared the impact of neonatal and adult hippocampal lesions on behavioral responses to MK-801, a noncompetitive NMDA antagonist. METHODS: Neonatal rats were lesioned on postnatal day 7. Their motor activity in response to MK-801 was tested at a juvenile age, in adolescence, and in adulthood. We also measured binding of [(3)H]MK-801 and the expression of NR1 messenger RNA (mRNA) in the medial prefrontal cortex and nucleus accumbens. Adult rats received similar lesions and were tested 4 and 8 weeks after the lesion. RESULTS: As juveniles, neonatally lesioned rats did not differ from control rats in responsiveness to MK-801, whereas in adolescence and adulthood they showed more pronounced hyperactivity than control rats. The adult lesion did not alter behaviors elicited by MK-801. Neonatally lesioned rats showed no apparent changes in [(3)H]MK-801 binding or expression of the NR1 mRNA. CONCLUSIONS: These results suggest that an early lesion of the ventral hippocampus affects development of neural systems involved in MK-801 action without changes at the NMDA receptor level, and they show that the behavioral changes manifest first in early adulthood.     

Alterations of hippocampal and prefrontal GABAergic interneurons in an animal model of psychosis induced by NMDA receptor antagonism

Some behavioral symptoms and neuropathological features of schizophrenia, like alterations of local GABAergic interneurons, could be emulated in an animal model of psychosis based on prolonged low-dose exposure to N-methyl-D-aspartate (NMDA) receptor antagonists, e.g. MK-801. Employing this model, we examined distinct subpopulations of GABAergic interneurons within the hippocampus and prefrontal cortex. Compared to saline control, animals receiving MK-801 exhibited a decreased density of hippocampal parvalbumin-positive interneurons. A co-administration of the antipsychotic drug haloperidol ameliorated this effect of MK-801 on PV(+) interneurons in the hippocampus, but led to a marked reduction of PV immunoreactivity in the prefrontal cortex, when comparing with saline, MK-801 or haloperidol treatment alone. Neither calretinin immunoreactivity nor nicotinamide adenine dinucleotide phosphate (NADPH)-diaphorase staining, representing neuronal nitric oxide synthase activity mostly detectable in interneurons, was altered by either treatment. With special reference to the hippocampus, these data show that a prolonged application of low-dose NMDA receptor antagonist could, in part, mimic some neuropathologic findings in human schizophrenia, thus strengthening the idea that (sub-) chronic NMDA receptor antagonism in animals is a viable approach in mimicking aspects of schizophrenia. Moreover, this study provides further evidence for regional differences in the response of GABAergic interneurons to NMDA receptor antagonism and antipsychotic treatment.     

Positive allosteric modulation of metabotropic glutamate 5 (mGlu5) receptors reverses N-Methyl-D-aspartate antagonist-induced alteration of neuronal firing in prefrontal cortex.

BACKGROUND: Several lines of evidence suggest that N-methyl-D-aspartate (NMDA) receptor hypofunction may be associated with schizophrenia. Activation of metabotropic glutamate 5 (mGlu5) receptors enhances NMDA receptor mediated currents in vitro, implying that allosteric modulation of mGlu5 receptors may have therapeutic efficacy for schizophrenia. The aim of this study was to determine if positive allosteric modulators of mGlu5 receptors are effective in reversing two cellular effects of NMDA receptor antagonists that are relevant to schizophrenia: increases in corticolimbic dopamine neurotransmission and disruption of neuronal activity in the prefrontal cortex (PFC). METHODS: In freely moving rats, we measured the effects of the positive modulator of mGlu5 receptor 3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) alone or in combination with the NMDA antagonist MK801 on 1) spontaneous firing and bursting of medial PFC (mPFC) neurons, and 2) dopamine release as measured by microdialysis in the mPFC and nucleus accumbens (NAc). RESULTS: The predominant effect of CDPPB on mPFC neurons was excitatory, leading to an overall excitatory population response. Pretreatment with CDPPB prevented MK801-induced excessive firing and reduced spontaneous bursting. In contrast, CDPPB had no significant effect on basal dopamine release as compared with control rats and did not alter MK801-induced activation of dopamine release in the mPFC and NAc. CONCLUSIONS: These results show that positive modulation of mGlu5 receptors reverses the effects of noncompetitive NMDA antagonists on cortical neuronal firing without affecting dopamine neurotransmission. Thus, these compounds may be effective in ameliorating PFC mediated behavioral abnormalities that results from NMDA receptor hypofunction.     

Erythropoietin protects the developing brain against N-methyl-D-aspartate receptor antagonist neurotoxicity

Pharmacological blockade of NMDA receptor function induces apoptotic neurodegeneration in the developing rat brain. However, the use of NMDA receptor antagonists as anesthetics and sedatives represents a difficult-to-avoid clinical practice in pediatrics. This warrants the search for adjunctive neuroprotective measures that will prevent or ameliorate neurotoxicity of NMDA receptor antagonists. The NMDA receptor antagonist MK801 triggered apoptosis in the neonatal rat forebrain, most notably in cortex and thalamus. MK801 exposure reduced mRNA levels of erythropoietin (EPO) and the EPO receptor, suggesting that loss of endogenous EPO activity may contribute to MK801-induced apoptosis. Coadministration of recombinant EPO (rEPO) conferred 50% neuroprotection, partially restored MK801-induced reduction of brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) mRNA, and prevented decreased phosphorylation levels of extracellular signal-regulated protein kinase-1/2 (ERK1/2) and Akt. These observations indicate that rEPO partly rescues newborn rats from MK801-mediated brain damage by enhancing neurotrophin-associated signaling pathways.     

Effects of antipsychotic treatments and D-serine supplementation on the electrophysiological activation of midbrain dopamine neurons induced by the noncompetitive NMDA antagonist MK 801

The acute administration of the noncompetitive glutamate N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine (MK 801) is known to increase central dopaminergic activity in rats and to elicit schizophreniform behavior in human. The current study was undertaken to compare the effects of different acute or chronic neuroleptic treatments, on the response of ventral tegmental area dopamine (DA) neurons to MK 801, using the in vivo electrophysiological paradigm in anesthetized preparations. Sprague Dawley male rats were treated, acutely or chronically during 3 weeks, with saline, olanzapine (10 mg/kg), haloperidol (1 mg/kg) or the combination of haloperidol with D-serine (1 mg/kg/300 mg/kg), a gliotransmitter coagonist of the NMDA receptor that has been shown to improve the efficacy of typical neuroleptics. In control animals, the acute administration of MK 801 (0.5 mg/kg, i.v.) increased significantly both the firing and burst activity of DA neurons by 20 and 26%, respectively, the latter effect being partially reversed by the selective 5-HT2A antagonist M 100,907 (0.4 mg/kg, i.v.). The acute preadministration of haloperidol (1 mg/kg, i.p.) and olanzapine (10 mg/kg, i.p.) failed to prevent or reverse the activatory effect of MK 801 on firing activity. On the other hand, MK 801-induced burst activity, was partially prevented by olanzapine, but not by haloperidol pretreatment. All antipsychotic treatments, when administered chronically, prevent the activatory effect of MK 801 on both firing and burst activity, and occasionally convert the response to MK 801 on burst activity to an inhibitory response, the latter occurring more predominantly in rats treated with the combination haloperidol/D-serine. These results suggest that a chronic antipsychotic regime alters the function of the NMDA receptors that tonically control the firing activity of midbrain dopaminergic neurons.     

Short and long term changes in NMDA receptor binding in mouse brain following chronic phencyclidine treatment

Summary Phencyclidine (PCP) is an antagonist of the NMDA subtype of glutamate receptor. PCP treatment induces psychosis in normal humans, which provides a valuable model of schizophrenia. PCP administration also models some of the symptoms of schizophrenia in experimental animals. NMDA hypofunction has been hypothesized to explain these schizophrenia-like symptoms. Acute or chronic administration of the NMDA receptor antagonist PCP has been shown to induce several short or long-term effects in both humans and experimental animals. In an attempt to clarify the neurochemical substrates of these effects in the present study, we used quantitative autoradiography to examine the effects of chronic (14 days) PCP treatment on NMDA receptor binding in mouse brain following both a short- (1 and 24 h) and long-term (14 days) delay after the last PCP treatment. NMDA receptors were targeted using [³H]MK801. Chronic PCP treatment increased [³H]MK801 binding consistently in the hippocampus in the short-term (p < 0.01). Conversely in the long-term, there were widespread reductions in NMDA receptor binding and this effect was most evident in the hippocampus where a 35% reduction of binding was found (p < 0.001). These results suggest that the hippocampus has a strong involvement in both the short and long-term effects of PCP treatment and that reduced NMDA receptor function might be one of the neurochemical substrates of the long lasting actions of PCP or PCP-induced psychosis. Importantly, this study shows that the long-term delay following chronic PCP treatment more accurately represents a state of NMDA hypofunction than the short-term PCP model.     

Pretreatment with NMDA receptor antagonist MK801 improves neurophysiological outcome after an acute spinal cord injury

Abstract

The post-traumatic release of excitatory amino acids (EAA) and their actions on N-methyl-D-aspartate (NMDA) receptors plays a major role in the spinal cord secondary injury process. The neuronal damage caused by the release of EAA may be reduced by NMDA-receptor channel blockers. To investigate the involvement of NMDA receptors in spinal cord injury (SCI), we pretreated animals with the noncompetitive NMDA antagonist MK801 (1.0 mg kg~before a compressive acute SCI. Pretreated animals with MK801 significantly (p = 0.038) improved the recovery of function as measured by evoked potential activities. Morphologically, specimens from rats treated with MK801 were characterized by milder and more localized hemorrhage in the gray matter. Immunohistochemical staining for glial fibrillary acidic protein (GFAP) and neurofilament (NF) histochemistry showed leakage of these antigens in traumatized cord while characteristic staining of astrocytes and neurons and their processes was observed in morphologically preserved tissue. The loss of NF immunoreactivity was reduced by MK801 treatment. [Neurol Res 1996; 18: 509-515]     

Comparison of the effects of NMDA antagonists on medial vestibular nucleus neurons in brainstem slices from labyrinthine-intact and chronically labyrinthectomized guinea pigs

The responses of ipsilateral medial vestibular nucleus (MVN) neurons in brainstem slices from guinea pigs compensated for a unilateral labyrinthectomy (UL), to the (NMDA) receptor/channel antagonists CPP and MK801, were compared with those of MVN neurons in brainstem slices from labyrinthine-intact guinea pigs observed in a previous study. The average resting activity of ipsilateral MVN neurons from compensated animals was significantly higher than that for MVN neurons from labyrinthine-intact animals; however, there were no significant differences in the average magnitude of the decrease in firing rate from baseline in response to CPP or MK801 and the only significant difference in the number of responses was to MK801, where fewer ipsilateral MVN neurons from compensated animals responded with a decrease in firing rate. These results suggest that vestibular compensation is not associated with an up-regulation or increased affinity of NMDA receptors in the MVN ipsilateral to the UL.     

Partial protection of hippocampal neurons by MK-801 during perforant path stimulation in the immature brain

We investigated whether the non-competitive NMDA receptor antagonist, MK-801, could protect neurons in the immature brain from the excitotoxic affects of perforant path stimulation. A high dose of MK-801 reduced the number of injured hilar interneurons in the stimulated hippocampus from 30.0±5.2 in unmedicated rats to 12.2±9.6 in MK-801 treated animals (P<0.05). MK-801 injection also protected the animals from the scattered dentate granule cell injury observed in non-medicated animals 1 day after stimulation. Other effects of drug injection included exacerbated damage in limbic cortices, retrosplenial cortical damage, and reduced inhibition in a highly epileptogenic region of the dentate gyrus. Our results show that a subpopulation of hilar interneurons is vulnerable to NMDA-induced damage in the immature hippocampus but that non-competitive blockade of the NMDA receptor may be a dangerous therapeutic strategy.© 1997 Elsevier Science B.V. All rights reserved.     

MK801 decreases glutamate release and oxidative metabolism during hypoglycemic coma in piglets.

Hypoglycemic coma increases extracellular excitatory amino acids, which mediate hypoglycemic neuronal degeneration. Cerebral oxygen consumption increases during hypoglycemic coma in piglets. We tested the hypothesis that the NMDA-receptor antagonist dizocilpine (MK801) attenuates the increase in cerebral oxygen consumption during hypoglycemia. We measured EEG, cerebral blood flow (CBF), cerebral oxygen consumption (CMRO(2)) and cortical microdialysate levels of glutamate, aspartate and glycine in pentobarbital-anesthetized piglets during 60 min of insulin-induced hypoglycemic coma. NMDA-receptor distribution was measured by autoradiography. MK801 (0.75 mg/kg i.v.) was given within 5 min after onset of isoelectric EEG. Saline- and MK801-treated normoglycemic control animals were also studied. Brain temperature was maintained at 38.5+/-0.5 degrees C. MK801 prevented the 5--10-fold increase in glutamate and aspartate occurring in saline-treated hypoglycemic animals, and attenuated the increase in CMRO(2). Increases in CBF of 200--400% during hypoglycemic coma were not affected by MK801. MK801 did not alter CBF, CMRO(2) or microdialysate amino acid levels in normoglycemic control animals. Parietal cortex corresponding to microdialysis sites was highly enriched in NMDA receptors, and the density and distribution overall of NMDA receptor binding sites were comparable to that reported in other species. We conclude that NMDA receptor activation plays a central role in hypoglycemia-induced glutamate release, and contributes to increased cerebral oxygen consumption. Neuroprotective effects of MK801 during hypoglycemia in piglets may involve inhibitory effects on glutamate release and oxidative metabolism.     

Interruption of functional recovery by the NMDA glutamate antagonist MK801 after compression of the sensorimotor cortex: implications for treatment of tumors or other mass-related brain injuries

Glutamate antagonists have recently been shown to limit tumor growth, providing potential new therapeutic targets and strategies against brain tumors. Here, we demonstrate that the glutamate NMDA receptor antagonist MK801, after a delay, adversely reverses functional recovery in rats with compressive mass lesions of the sensorimotor cortex. Our data suggest that the controlled focal cortical compression model may be a valuable pre-clinical tool to screen compounds for the treatment of brain tumors. It may be possible to use this model to develop interventions that maintain anti-cancer effects but with diminished harm to bystander tissue and brain plasticity.     

Effects of MK-801 upon local cerebral glucose utilisation in conscious rats following unilateral lesion of caudal entorhinal cortex

Local cerebral glucose utilisation was examined in 62 discrete regions of conscious rats following unilateral ibotenic acid lesion of the caudal entorhinal cortex, and subsequent pharmacological challenge with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Fourteen days after unilateral lesion of the entorhinal cortex, there were no significant alterations in local cerebral glucose use except within the lesioned entorhinal cortex (reduced by 31% compared to sham-operated control animals). In sham-operated animals, systemic administration of MK-801 (0.5 mg/kg, i.v.) induced anatomically organised alterations in glucose use with increases in olfactory areas, subicular complex and some limbic areas (posterior cingulate cortex, mammillary body and anteroventral thalamic nucleus), and decreases in the inferior colliculus and neocortex (auditory, sensory-motor, somatosensory and frontal cortices). In animals with unilateral entorhinal cortex lesions, the metabolic response to MK-801 differed significantly from the response to the drug in sham-lesioned animals in a number of regions, viz. hippocampus, molecular layer (ipsilateral to lesion), entorhinal cortex (ipsilateral), dentate gyrus (ipsilateral), presubiculum (bilateral), parasubiculum (bilateral) and nucleus accumbens (bilateral). The ability of MK-801 to reduce glucose use in the neocortex was not altered by entorhinal cortex lesion. These data suggest that the functional consequences of non-competitive NMDA receptor blockade are dependent in some areas upon the integrity of the perforant pathway from the entorhinal cortex to the hippocampus.     

Effect of ethanol on phosphorylation of the NMDAR2B subunit in mouse cortical neurons.

There is evidence that phosphorylation plays a crucial role in the regulation of the NMDA receptors in the brain. In this study we examined the effect of acute and chronic ethanol treatment on the phosphorylation of the R2B subunit of the NMDA receptors in fetal cortical neurons. Additionally, the effect of acute ethanol treatment on the phosphorylation of the R2B subunit in adult cerebral cortex and hippocampus was also examined. The results show that acute or chronic ethanol treatments did not affect the total phosphorylation of the R2B subunit in cortical neurons. In adult mice, we observed that acute ethanol treatment increased the tyrosine phosphorylation of the R2B subunit in hippocampus but not in cerebral cortex. We also observed that acute or chronic ethanol treatments did not alter the Fyn or Csk levels in cortical neurons. Although Fyn, but not Csk, was present in adult cerebral cortex, ethanol did not phosphorylate the R2B subunit in this region. Like ethanol, MK-801 (NMDA antagonist) did not affect the phosphorylation of the R2B subunit in cortical neurons. Taken together, these results suggest that acute and chronic ethanol and MK-801 treatments do not affect the phosphorylation of the R2B subunit in fetal cortical neurons and adult cerebral cortex. Based on these observations, we speculate that the R2B subunit of the NMDA receptors is regulated by multiple cascades and in a brain region specific manner.     

MK801 induces late regional increases in NMDA and kainate receptor binding in rat brain

Summary We have previously shown that a single dose of PCP produces a dose-related increase in NMDA-sensitive³H-glutamate binding in CA₁ of hippocampus 24 hours later, and some regional changes in kainate binding. Here we report that dizocilpine (MK 801) (O.1 mg/kg and 1 mg/kg), a selective agonist at the PCP receptor and a noncompetitive antagonist of NMDA, produces a similar increase in NMDA-sensitive glutamate and kainate receptor binding in hippocampus 24 hours after a dose. These observations support the conclusion that blockade of glutamate-mediated transmission at the NMDA receptor selectively increases NMDA-sensitive glutamate receptor binding in CA₁ of hippocampus and kainate binding in CA₃ and dentate gyrus at putatively delayed time points. Several additional areas outside of hippocampus also showed receptor changes at 24 hours after MK801.     

NMDA and benzodiazepine receptors have synergistic and antagonistic effects on precursor cells in adult hippocampal neurogenesis

We studied how the noncompetitive NMDA receptor antagonist MK801 affected different stages of adult hippocampal neurogenesis in mice, and investigated how the activation of benzodiazepine receptors with diazepam interacted with the effects of MK801 on the precursor cells in the adult dentate gyrus. Our findings were: (i) one single MK801 application increased precursor cell proliferation and adult neurogenesis but not gliogenesis 4 weeks later; (ii) the number of label-retaining precursor cells decreased after MK801 (with P  = 0.06); (iii) the pro-neurogenic effect included increased cell cycle entry of precursor cells as well as completed cell divisions, except in type-2a cells; (iv) NMDA receptor blockade also increased the number of nestin–GFP-expressing cells expressing calretinin; (v) diazepam alone had a very similar effect on overall precursor cell proliferation to that of MK801 alone; and (vi) diazepam, when co-applied with MK801, abolished the suppression of divisions of type-2a cells induced by MK801 alone, suppressed the MK801-induced effect on proliferation of type-2b cells and had no influence on the effects of MK801 on type-3 cells, but did suppress the increased number of nestin–GFP-positive cells expressing calretinin. From these results we hypothesize that, depending on the precursor cell stage, NMDA-dependent neurotransmission has distinct effects that are partly antagonized and partly enhanced by GABAergic input. We propose that NMDA receptor-dependent signalling maintains the precursor cells in the dentate gyrus while blocking initial stages of development and promoting more advanced stages.     

NMDA receptor blockade and hippocampal neuronal loss impair fear conditioning and position habit reversal in C57Bl/6 mice

The interpretation of learning and memory deficits in transgenic mice has largely involved theories of NMDA receptor and/or hippocampal function. However, there is little empirical data that describes what NMDA receptors or the hippocampus do in mice. This research assessed the effects of different doses of the NMDA receptor antagonist, MK-801, or different-sized hippocampal lesions on several behavioral parameters in adult male C57Bl/6 mice. In the first set of experiments, different doses of MK-801 (0.05-0.3mg/kg, s.c.) were assayed in fear conditioning, shock sensitivity, locomotion, anxiety, and position habit reversal tests. Contextual and cued fear conditioning, and position habit reversal were impaired in a dose-dependent manner. Locomotor activity was increased immediately after injection of the highest dose of MK-801. A second set of experiments determined the behavioral effects of a moderate and large excitotoxic hippocampal lesion. Both lesions impaired contextual conditioning, while the larger lesion interfered with cued conditioning. Reversal learning was significantly diminished by the large lesion, while the moderate lesion had a detrimental effect at a trend level (P<0.10). These results provide important reference data for studies involving genetic manipulations of NMDA receptor or hippocampal function in mice. Furthermore, they serve as a basis for a non-transgenic mouse model of the NMDA receptor or hippocampal dysfunction hypothesized to occur in human cognitive disorders.