Expression of the NR2B-NMDA receptor subunit and its Tbr-1/CINAP regulatory proteins in postmortem brain suggest altered receptor processing in schizophrenia.
Several lines of evidence implicate aberrant glutamate neurotransmission in the pathophysiology of schizophrenia. In particular, compromised signaling through the N-methyl-D-aspartate (NMDA) receptor has been linked to positive, negative, and cognitive symptoms of this illness. Studies in postmortem brain have identified altered expression of several structural and signaling molecules of the postsynaptic density (PSD), including the abundantly expressed protein PSD-95, which binds directly to NR2 subunits of the NMDA receptor and regulates its trafficking, membrane expression, and downstream signaling. Several mechanisms for functional regulation of the NR2B-containing NMDA receptor, which have been linked to cognitive dysfunction in schizophrenia, are well known. To analyze whether early events in NR2B processing are affected in schizophrenia, we have isolated a subcellular endoplasmic reticulum (ER)-enriched fraction from postmortem brain and analyzed expression of the NR1 and NR2B NMDA receptor subunits as well as PSD-95 in two areas of prefrontal cortex. We found significantly decreased ER expression of NR2B and PSD-95 in dorsolateral prefrontal cortex in schizophrenia. Analysis in total-cell homogenates from the same subjects of NR2B and PSD-95 expression, as well as of the CINAP and Tbr-1 transcription regulatory proteins, indicate that changes in NR2B processing in schizophrenia involve increased ER exit of NR2B containing NMDA receptors.
Kristiansen
Lars V
LV
Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, Alabama, USA. villiam68@gmail.com
Patel
Sagar A
SA
Haroutunian
Vahram
V
Meador-Woodruff
James H
JH
D000368:Aged; D000369:Aged, 80 and over; D015153:Blotting, Western; D016022:Case-Control Studies; D004268:DNA-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; D004721:Endoplasmic Reticulum / Q000378:metabolism; D005260:Female; D006179:Gyrus Cinguli / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D008875:Middle Aged; D009687:Nuclear Proteins / Q000378:metabolism*; D017397:Prefrontal Cortex / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D012559:Schizophrenia / Q000378:metabolism*; D020825:T-Box Domain Proteins / Q000378:metabolism*
C501444:DLG4 protein, human; D004268:DNA-Binding Proteins; D000076122:Disks Large Homolog 4 Protein; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C409466:NR1 NMDA receptor; C121001:NR2B NMDA receptor; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D020825:T-Box Domain Proteins; C108625:TBX1 protein, human; C432963:TSPYL2 protein, human