Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain

Ikonomidou, Chrysanthy; Bosch, F R van den; Miksa, Michael; Bittigau, Petra; Vöckler, Jessica; Dikranian, Krikor; Tenkova, Tatyana; Stefovska, Vanya; Turski, Lechosław; Olney, John W.

doi:10.1126/science.283.5398.70

Cited by 1,909 publications

(1,492 citation statements)

References 29 publications

Supporting

Mentioning

1,376

Contrasting

Unclassified

Order By: Relevance

“…These results demonstrate how crucial NMDA receptor activation is in synaptogenesis, and emphasizes the importance of NMDA receptors in synaptic plasticity (Brooks et al, 1997). In the immature rat brain, blockade of NMDA receptors for only a few hours during late fetal or early neonatal life increases the normal apoptotic neurodegeneration process (Ikonomidou et al, 1999). The 7-10 day window appears to be critical, with even brief exposure to NMDA receptor antagonists resulting in deleterious effects on CNS development and function (Haberny et al, 2002).…”

Section: Introductionmentioning

confidence: 81%

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Andersen

Pouzet

2004

Neuropsychopharmacol

119

View full text Add to dashboard Cite

It has been suggested that perinatal treatment with the noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist phencyclidine (PCP) induces transient neurodegeneration in the limbic and cortical structures of rats. Since dysfunction of these structures is associated with cognitive deficits in patients with schizophrenia, we studied the effects of subchronic treatment with PCP in perinatal rats with respect to spatial reference, reversal, and spatial working memories using the Morris water maze task in adulthood. In addition, we investigated the effect of D-serine, which has clinical relevance for the treatment of cognitive deficits in patients with schizophrenia. Our goal was to develop a neurodevelopmental model with predictive validity for the cognitive dysfunction described in patients with schizophrenia. Male and female Sprague-Dawley rats were treated with either saline or PCP (8.7 mg/kg s.c.) on days 7, 9, and 11, postnatal, and the long-term behavioral effects were investigated in adulthood. Male PCP-treated rats were slightly impaired during the spatial reference memory task, but strongly impaired during the reversal and spatial working memory tasks. Female rats were not significantly affected by this treatment. This cognitive deficit was reversed by chronic treatment with D-serine. We suggest that this model mimics some of the cognitive deficits of patients with schizophrenia and might be appropriate for the screening of putative antipsychotic agents for the treatment of these cognitive deficits.

show abstract

Section: Introductionmentioning

confidence: 81%

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Andersen

Pouzet

2004

Neuropsychopharmacol

119

View full text Add to dashboard Cite

show abstract

“…they show preference for superficially located pyramidal neurons. Compared to pyramidal neurons located in deeper cortical layers, these superficially located pyramids migrate and differentiate late in cortical development (Rakic, 1981) and their vulnerability to NMDA blockade in mature animals can be viewed as a persisting developmental profile of susceptibility to NMDA receptor antagonism (Ikonomidou et al, 1999). In light of the fact that this developmental susceptibility tends to produce a morphologically apoptotic type of degeneration, MK801-induced degeneration of pyramidal neurons in the adult piriform cortex is closer to a developmental degenerative profile.…”

Section: Discussionmentioning

confidence: 99%

NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons

et al. 2007

View full text Add to dashboard Cite

Pyramidal relay neurons in limbic cortex are vulnerable to denervation lesions, i.e. pyramidal neurons in layer IIα of piriform cortex undergo transsynaptic apoptosis after lesions that interrupt their inputs from the olfactory bulb. We have previously established the role of inhibitory interneurons in elaborating signals that lead to the apoptosis of projection neurons in these lesion models, i.e. the upregulation of neuronal NOS and release of nitric oxide. Thus, we have proposed that cortical interneurons play an essential role in transducing injury to degenerative effects for nearby pyramidal neurons. In the present study, we extend the previous findings to a toxic model of degeneration of pyramidal neurons in the adult paralimbic cortex, i.e. after exposure to the NMDA channel blocker MK801. Our findings indicate that treatment of adult rats with MK801 in doses previously found to cause alterations in pyramidal neurons of the retrosplenial cortex (5 mg/kg) results in an active caspase 3 (+), ultrastructurally apoptotic type of cell death involving the same projection neurons of layer IIα that are also vulnerable to bulbotomy lesions. Interneurons of layer I are induced by MK801 treatment to higher levels of nNOS expression and the selective nNOS inhibitor BRNI ameliorates pyramidal cell apoptosis caused by MK801. Our results indicate that certain pyramidal neurons in piriform cortex are very sensitive to NMDA blockade as they are to disconnection from modalityspecific afferents and that inhibitory interneurons play significant roles in mediating various types of pro-apoptotic insults to cortical projection neurons via nNOS/NO signaling.

show abstract

“…Of great interest in terms of neurodevelopment are data that NMDA receptors are important for certain aspects of neuronal development, including axonal guide pathways, migration, and differentiation, with the mediating factor thought to be Ca2+ influx Rakic 1993, 1998). An important addition to this literature was the recent report by Ikonomidou et al (1999), demonstrating that apoptotic neuronal death in the pre-and perinatal period occurs with the application of NMDA channel blockers (e.g. MK801, PCP, ketamine, and carboxypiperazin-4-yl-propyl-1-phosphonic acid (CPP)).…”

Section: Cellular Circuit Abnormalities In Schizophrenia: a Failure Omentioning

confidence: 99%

“…It may seem paradoxical that application of blockers of excitatory NMDA neurotransmission has the capability of causing excitotoxic effects (Ikonomidou et al 1999). However, studies by Grunze et al (1996) in our laboratory indicate this paradox may be resolved by the differential sensitivity of NMDA receptors on inhibitory interneurons and those involved in feed-forward excitation.…”

Section: Mechanism Of Nmda Action: Decrease In Recurrent Inhibitionmentioning

confidence: 99%

Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects

McCarley

Niznikiewicz

Salisbury

et al. 1999

European Archives of Psychiatry and Clinical Neurosciences

View full text Add to dashboard Cite

Seeking to unite psychological and biological approaches, this paper links cognitive and cellular hypotheses and data about thought and language abnormalities in schizophrenia. The common thread, it is proposed, is a dysregulated suppression of associations (at the behavioral and functional neural systems level), paralleled by abnormalities of inhibition at the cellular and molecular level, and by an abnormal anatomical substrate (reduced MRI gray matter volume) in areas subserving language.At the level of behavioral experiments and connectionist modeling, data suggest an abnormal semantic network connectivity (strength of associations) in schizophrenia, but not an abnormality of network size (number of associates). This connectivity abnormality is likely to be a preferential processing of the dominant (strongest) association, with the neglect of preceding contextual information.At the level of functional neural systems, the N400 event-related potential amplitude is used to index the extent of "search" for a semantic match to a word. In a short stimulus-onset-asynchrony condition, both schizophrenic and schizotypal personality disorder subjects showed, compared with controls, a reduced N400 amplitude to the target words that were related to cues, e.g. cat-dog, a result compatible with behavioral data. Other N400 data strongly and directly suggest that schizophrenics do not efficiently utilize context. At the level of anatomical system substrates, considerable MRI data indicate abnormalities in the temporal lobe structures that subserve language and verbal associations. Gray matter volume is reduced in the posterior portion of the dominant superior temporal gyrus in both chronic and first episode schizophrenics (but not in manic-depressive psychosis), with the magnitude of reduction correlating with the degree of thought disorder.At the level of in vitro cellular and molecular analysis, NMDA receptors on inhibitory neurons are much more sensitive to blockade than are excitatory projections. A resulting failure of recurrent inhibition may account for the psychotomimetic effects of such NMDA receptor blockers as ketamine and phencyclidine, and may also be present in schizophrenia, where an endogenous NMDA receptor blocker, NAAG, is increased, and where other abnormalities of recurrent inhibition may be present. A biophysical simulation of this circuit abnormality in a model of learned pattern recognition produced, because of the reduction in recurrent inhibition, aberrant spread of excitation, resulting in confusion of normally distinguishable patterns. We suggest the neural circuit failure of inhibition and consequent aberrant spread of activation may be the substrate for an inability to use context, with the behavioral and functional consequences just described. Furthermore, there is the possibility that the unbalanced excitation might lead to progressive, neurodegenerative changes in gray matter, marked by progressive volume reduction.

show abstract

Blockade of NMDA Receptors and Apoptotic Neurodegeneration in the Developing Brain

Cited by 1,909 publications

References 29 publications

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

Spatial Memory Deficits Induced by Perinatal Treatment of Rats with PCP and Reversal Effect of D-Serine

NMDA inhibitors cause apoptosis of pyramidal neurons in mature piriform cortex: Evidence for a nitric oxide-mediated effect involving inhibitory interneurons

Cognitive dysfunction in schizophrenia: unifying basic research and clinical aspects

Contact Info

Product

Resources

About