Altered transcript expression of NMDA receptor-associated postsynaptic proteins in the thalamus of subjects with schizophrenia.
OBJECTIVE
NMDA receptor dysfunction has been implicated in the pathophysiology of schizophrenia. The NMDA receptor is a multimeric ligand-gated ion channel, and the obligate NR(1) subunit is expressed as one of eight isoforms due to the alternative splicing of exons 5, 21, and 22. Alternative splicing of NR(1) subunits modulates receptor function by influencing the association of NR(1) with other NMDA receptor subunits and myriad intracellular molecules, such as the postsynaptic density family of proteins that target NMDA receptors to the synaptic membrane and couple it to numerous signal transduction enzymes. Recently, the authors reported that the NMDA receptor subunits NR(1) and NR(2C) are abnormally expressed in the thalamus in schizophrenia. They hypothesized that this reduction is associated with specific NR(1) isoforms and that NMDA receptor-related postsynaptic density proteins are abnormally expressed.


METHODS
Using in situ hybridization, the authors examined expression of the transcripts encoding NR(1) isoforms containing exons 5, 21, or 22, and the NMDA receptor-related postsynaptic density proteins NF-L, PSD93, PSD95, and SAP102.


RESULTS
Reduced NR(1) subunit transcript expression was restricted to exon 22-containing isoforms. Increased expression of the NMDA receptor-associated postsynaptic density proteins NF-L, PSD95, and SAP102 was also detected in the thalamus of subjects with schizophrenia.


CONCLUSIONS
These data support the hypothesis of glutamatergic abnormalities in schizophrenia and suggest that glutamatergic dysfunction may occur not only at the level of receptor expression but also within intracellular pathways associated with glutamate receptor-associated signal transduction.
Clinton
Sarah M
SM
Department of Psychiatry and Mental Health Research Institute, Universiyt of Michgan medical School, MI 48109-0720, USA. clintons@umich.edu
Haroutunian
Vahram
V
Davis
Kenneth L
KL
Meador-Woodruff
James H
JH
D000368:Aged; D000076122:Disks Large Homolog 4 Protein; D005091:Exons / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016900:Neurofilament Proteins / Q000378:metabolism; D009479:Neuropeptides / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D009687:Nuclear Proteins; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D000074407:SAP90-PSD95 Associated Proteins; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D015398:Signal Transduction / Q000235:genetics; D013788:Thalamus / Q000378:metabolism*; D014157:Transcription Factors; D014158:Transcription, Genetic
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; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D020033:Protein Isoforms; D016194:Receptors, N-Methyl-D-Aspartate; D000074407:SAP90-PSD95 Associated Proteins; D014157:Transcription Factors; C044882:neurofilament protein L; C033652:postsynaptic density proteins