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.