Localization of NMDA receptors in the cerebral cortex: a schematic overview

Conti, Fiorenzo

doi:10.1590/s0100-879x1997000500001

Cited by 27 publications

(16 citation statements)

References 60 publications

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“…For NR2A-D, our present protein data are consistent with previous reports of unaltered expression of these subunits at the transcriptional level. NR2C expression in PFC is generally quite low 64 and a small decrease of this subunit mRNA, as reported previously, might not be detected on the protein level. The observed increase in NR1 C2 0 expression in ACC in the present work likely was detected as a result of differentiating between the two NR1 C2-terminal variants.…”

Section: Discussionsupporting

confidence: 45%

“…81 These projections to cortical layer IV likely interact primarily with non-NMDA receptor targets, as NMDA receptor expression is less abundant in layer IV than in layers II-III and V-VI. 64 Owing to the layer-related differences in the expression of NMDA receptors in the frontal cortex, our observation of abnormal NMDA-related protein expression in schizophrenia therefore might suggest that the abnormalities of cortical NMDA-related circuitry primarily is of corticocortical nature. Through the complex connectivity of pyramidal neurons in the frontal cortex, consisting of layer II-III neurons projecting between cortical regions, the larger pyramidal neurons of layer V projecting to the thalamus, and layer VI neurons projecting to the hippocampus and striatum among other subcortical structures, the present findings of NMDA-related abnormalities in schizophrenia either directly or indirectly link with other areas affected in this psychiatric illness.…”

Section: Functional Implications Of Nmda-related Alterationsmentioning

confidence: 89%

“…43 Despite the fact that different cell types in all cortical layers express NMDA receptors, 79 pyramidal cells account for approximately 70% of NMDA receptor expression in the frontal cortex. 64,80 The primary afferent input to the frontal cortex is from thalamocortical projections, with synaptic endings in cortical layer IV. 81 These projections to cortical layer IV likely interact primarily with non-NMDA receptor targets, as NMDA receptor expression is less abundant in layer IV than in layers II-III and V-VI.…”

Section: Functional Implications Of Nmda-related Alterationsmentioning

confidence: 99%

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Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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Abnormal expression of the N-Methyl-D-Aspartate (NMDA) receptor and its interacting molecules of the postsynaptic density (PSD) are thought to be involved in the pathophysiology of schizophrenia. Frontal regions of neocortex including dorsolateral prefrontal (DLPFC) and anterior cingulate cortex (ACC) are essential for cognitive and behavioral functions that are affected in schizophrenia. In this study, we have measured protein expression of two alternatively spliced isoforms of the NR1 subunit (NR1 C2 and NR1 C2 0 ) as well as expression of the NR2A-D subunits of the NMDA receptor in DLPFC and ACC in post-mortem samples from elderly schizophrenic patients and a comparison group. We found significantly increased expression of NR1 C2 0 but not of NR1 C2 in ACC, suggesting altered NMDA receptor cell membrane expression in this cortical area. We did not find significant changes in the expression of either of the NR1 isoforms in DLPFC. We did not detect changes of any of the NR2 subunits studied in either cortical area. In addition, we studied expression of the NMDAinteracting PSD molecules NF-L, SAP102, PSD-95 and PSD-93 in ACC and DLPFC at both transcriptional and translational levels. We found significant changes in the expression of NF-L in DLPFC, and PSD-95 and PSD-93 in ACC; increased transcript expression was associated with decreased protein expression, suggesting abnormal translation and/or accelerated protein degradation of these molecules in schizophrenia. Our findings suggest abnormal regional processing of the NMDA receptor and its associated PSD molecules, possibly involving transcription, translation, trafficking and protein stability in cortical areas in schizophrenia.

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Section: Discussionsupporting

confidence: 45%

Section: Functional Implications Of Nmda-related Alterationsmentioning

confidence: 89%

Section: Functional Implications Of Nmda-related Alterationsmentioning

confidence: 99%

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Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

et al. 2006

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“…Some recent evidence suggests that the interpretation of the results of studies with uncompetitive NMDA antagonists may be more complex and that the symptoms induced by ketamine could be a result of increased glutamate release and/or increased activation of postsynaptic glutamate receptors (24). Because of the presynaptic localization of some NMDA receptors (51,54), a hyperglutamatergic state and increased glutamate release could result from ketamine administration and its interaction with presynaptic NMDA receptor elements (54,96). The increased glutamate release could then act on postsynaptic glutamatergic receptors (e.g., AMPA) and provoke the psychotomimetic symptoms observed with glutamate receptor antagonists.…”

Section: Discussionmentioning

confidence: 99%

N-Methyl-d-Aspartic Acid Receptor Expression in the Dorsolateral Prefrontal Cortex of Elderly Patients With Schizophrenia

Dracheva

Marras²,

Elhakem³

et al. 2001

AJP

179

103

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Objective:The N-methyl-D-aspartic acid (NMDA) class of glutamate receptors has received attention in the pathophysiology of schizophrenia because of the similarity between some schizophrenic symptoms and symptoms caused by NMDA antagonists. To determine if NMDA receptor abnormalities were present at the mRNA level, expression of NMDA receptor (NR) subunits NR 1 , NR 2A , and NR 2B was measured in specimens from the dorsolateral prefrontal cortex and the occipital cortex of elderly patients with schizophrenia and normal elderly subjects.Method: Postmortem specimens from antemortem assessed and diagnosed elderly patients with schizophrenia (N=26) were compared with those from a neuropathologically and neuropsychiatrically normal elderly comparison group (N=13) and from patients with Alzheimer's disease (N=10). The mRNA expression of the NR 1 , NR 2A , and NR 2B subunits and of postsynaptic density 95 (PSD-95), a protein associated with postsynaptic NMDA receptors, was studied with quantitative real-time reverse transcriptase polymerase chain reaction.Results: Expression of NR 1 and NR 2A but not NR 2B subunits was higher in the dorsolateral prefrontal cortex and the occipital cortex of patients with schizophrenia than in the normal and Alzheimer's disease groups. In contrast, NR 1 expression was significantly lower in the Alzheimer's disease group. Occipital cortex expression of PSD-95 was higher in the schizophrenic subjects and correlated strongly with the expression of NR 2A and NR 2B in both cortical regions and with expression of NR 1 in the occipital cortex. These results were not influenced by neuroleptic exposure history, postmortem interval, or age of the subject.Conclusions: NMDA receptor subunits are abnormally expressed in elderly patients with schizophrenia. The disproportionate expression of the NR 1 and NR 2A subunits relative to NR 2B expression may have implications for the pathophysiology of schizophrenia and the sensitivity of schizophrenic patients to glutamate and glutamatergic drugs. Several neurochemical hypotheses have been proposed to explain the origin of schizophrenia, including abnormal dopamine, serotonin (5-HT), γ-aminobutyric acid (GABA), and/or glutamate neurotransmission in different regions of the brain (1-8). Abnormalities in the dorsolateral prefrontal cortex have figured prominently in many of these hypotheses, in part due to results of in vivo imaging and neuroanatomical studies (9-11), although there is evidence for structural, metabolic, and neurochemical abnormalities in many other brain regions, including the thalamus, the hippocampus, and the cingulate and entorhinal cortices (1,(12)(13)(14)(15)(16)(17)(18)(19).Strong evidence supporting an association between glutamatergic hypofunction and schizophrenia has come from pharmacological studies showing that N-methyl-Daspartic acid (NMDA) receptor antagonists such as phencyclidine and ketamine can induce many of the psychotic signs and symptoms of schizophrenia in normal subjects, as well as exacerbate these signs and symptom...

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“…In general, NMDA receptors are found in many but not all cerebral cortex neurons and some cortical astrocytes [178,186] and play major roles in both physiological and pathological states of the CNS. Inappropriate activation of NMDA receptors has been stated in the etiology of various disorders.…”

Section: Nmda Receptorsmentioning

confidence: 99%

Ion Channels as Drug Targets in Central Nervous System Disorders

Waszkielewicz¹,

Gunia²,

Szkaradek³

et al. 2013

CMC

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Ion channel targeted drugs have always been related with either the central nervous system (CNS), the peripheral nervous system, or the cardiovascular system. Within the CNS, basic indications of drugs are: sleep disorders, anxiety, epilepsy, pain, etc. However, traditional channel blockers have multiple adverse events, mainly due to low specificity of mechanism of action. Lately, novel ion channel subtypes have been discovered, which gives premises to drug discovery process led towards specific channel subtypes. An example is Na + channels, whose subtypes 1.3 and 1.7-1.9 are responsible for pain, and 1.1 and 1.2 -for epilepsy. Moreover, new drug candidates have been recognized. This review is focusing on ion channels subtypes, which play a significant role in current drug discovery and development process. The knowledge on channel subtypes has developed rapidly, giving new nomenclatures of ion channels. For example, Ca 2+ channels are not any more divided to T, L, N, P/Q, and R, but they are described as Ca v 1.1-Ca v 3.3, with even newer nomenclature 1A-1I and 1S. Moreover, new channels such as P2X1-P2X7, as well as TRPA1-TRPV1 have been discovered, giving premises for new types of analgesic drugs.

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Localization of NMDA receptors in the cerebral cortex: a schematic overview

Cited by 27 publications

References 60 publications

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia

N-Methyl-d-Aspartic Acid Receptor Expression in the Dorsolateral Prefrontal Cortex of Elderly Patients With Schizophrenia

Ion Channels as Drug Targets in Central Nervous System Disorders

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