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

Abstract

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...

Postmortem Brain: An Underutilized Substrate for Studying Severe Mental Illness

“…Despite accounting for these factors, postmortem studies may find inconsistent results for the same dependent variable. For example, expression of mRNA for the GluN1 subunit of the NMDA glutamate receptor in the frontal cortex in schizophrenia was decreased (Sokolov, 1998), increased (Dracheva et al, 2001; Le Corre et al, 2000), and unchanged (Akbarian et al, 1996) in separate studies using tissues from different brain collections. Such disparate findings may be attributed to differences in methodology, variation in dissection protocols, and differences in the biological substrate due to the heterogeneity of the illness being studied.…”

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

“…35,37 These studies found no changes in transcript expression for NR2A, NR2B and NR2D, a small but significant decrease for NR2C in the frontal cortex in schizophrenia, and identified increased transcript expression for NR2A and PSD-95 in occipital cortex. 35 In addition, these studies reported either increased or unchanged expression of the NR1 transcript, which might be attributed to a difference in the prefrontal cortical area studied (Brodmann area 10 vs 46). For NR2A-D, our present protein data are consistent with previous reports of unaltered expression of these subunits at the transcriptional level.…”

“…[31][32][33][34] Changes in the expression of transcripts encoding NMDA receptor subunits in the prefrontal cortex have previously been described in post-mortem schizophrenic brains. [35][36][37] However, relatively little is known about protein expression of these subunits in schizophrenia. Additionally, expression of the NMDA receptor-interacting PSD molecules in schizophrenia have to date only been analyzed on transcriptional level, and primarily in subcortical regions in post-mortem brain.…”

Elevated GRIA1 mRNA expression in Layer II/III and V pyramidal cells of the DLPFC in schizophrenia

“…Studies are currently underway to assess NMDA and AMPA receptor subunit mRNA expression in the entorhinal cortex of individuals from the Neuropathology Consortium collection of the Stanley Medical Research Institute as well as a separate cohort. Finally, a number of studies have reported regional and laminar alterations in NMDA and AMPA receptor trafficking proteins in the DLPFC (Beneyto and MeadorWoodruff, 2006;Dracheva et al, 2001;Dracheva et al, 2005), providing insight into additional mechanism of glutamate dysregulation in this region. Due to limitations in resource material, we were unable to assess alterations in the mRNAs encoding glutamate receptor trafficking proteins in these cells.…”

“…Previous studies have examined the expression of NMDA and AMPA receptor subunits in the DLPFC and report increased NR1 (Dracheva et al, 2001), NR2D (Akbarian et al, 1996), and GluR1, decreased GluR2 Vawter et al, 2002), and increased (Dracheva et al, 2005) and/or decreased (Beneyto and MeadorWoodruff, 2006) GluR4 subunit mRNA expression in the DLPFC of schizophrenics. Other studies report no change in NMDA receptor mRNA or protein (Kristiansen et al, 2006) or AMPA receptor subunit mRNA (Healy et al, 1998;O'Connor et al, 2007).…”