Changes in NMDA receptor subunits and interacting PSD proteins in dorsolateral prefrontal and anterior cingulate cortex indicate abnormal regional expression in schizophrenia.
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 (NR1C2 and NR1C2') 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 NR1C2' but not of NR1C2 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 NMDA-interacting 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.
Kristiansen
L V
LV
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL 35294-0017, USA. larsk@uab.edu
Beneyto
M
M
Haroutunian
V
V
Meador-Woodruff
J H
JH
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D015870:Gene Expression; D051528:Guanylate Kinases / Q000235:genetics / Q000378:metabolism; D006179:Gyrus Cinguli / Q000502:physiology*; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics* / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D017397:Prefrontal Cortex / Q000502:physiology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics* / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism / Q000503:physiopathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
C116869:DLG3 protein, human; C501444:DLG4 protein, human; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; C044882:neurofilament protein L; C033652:postsynaptic density proteins; C496468:DLG2 protein, human; D051528:Guanylate Kinases