Abnormalities of the NMDA Receptor and Associated Intracellular Molecules in the Thalamus in Schizophrenia and Bipolar Disorder.
Several lines of investigation support a hypothesis of glutamatergic dysfunction in schizophrenia, including our recent reports of altered NMDA receptor subunit and associated intracellular protein transcripts in the thalamus of elderly patients with schizophrenia. In the present study, we used in situ hybridization to measure the expression of NMDA subunits (NR1, NR2A-D), and associated intracellular proteins (NF-L, PSD95, and SAP102) in a second, younger cohort from the Stanley Foundation Neuropathology Consortium, which included patients with both schizophrenia and affective disorders. We wanted to determine whether glutamatergic abnormalities in the thalamus in schizophrenia are present at younger ages, and whether these abnormalities occur in other psychiatric illnesses. In the present work, we observed increased expression of NMDA NR2B subunit transcripts, and decreased expression of all three associated postsynaptic density protein transcripts in schizophrenia. We also found evidence of glutamatergic dysfunction in the thalamus in affective disorders, particularly in bipolar disorder. In particular, we found decreased NF-L, PSD95, and SAP102 transcripts in bipolar disorder, and decreased SAP102 levels in major depression. Interestingly, one of the most consistent findings across diagnostic groups was an abnormality of intracellular signaling molecules that are linked to the NMDA receptor, rather than changes in the receptor subunits themselves. PSD95 and similar scaffolding molecules link the NMDA receptor with intracellular enzymes that mediate signaling, and also provide a physical link between different neurotransmitter systems to coordinate and integrate information from multiple effector systems. Abnormalities of PSD95-like molecules and other intracellular signaling machinery may contribute to dysregulated communication between multiple neurotransmitter systems (such as glutamatergic and dopaminergic systems) that are potentially involved in the neurobiology of schizophrenia and affective disorders.
Clinton
Sarah M
SM
Department of Psychiatry, Mental Health Research Institute, University of Michigan Medical School, Ann Arbor, MI 48109-0720, USA. clintons@umich.edu
Meador-Woodruff
James H
JH
D000328:Adult; D000368:Aged; D000704:Analysis of Variance; D001714:Bipolar Disorder / Q000235:genetics / Q000378:metabolism*; D016022:Case-Control Studies; D000076122:Disks Large Homolog 4 Protein; D005260:Female; D015870:Gene Expression; D006801:Humans; D017403:In Situ Hybridization / Q000379:methods; D047908:Intracellular Signaling Peptides and Proteins; D042541:Intracellular Space / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D016900:Neurofilament Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D012559:Schizophrenia / Q000235:genetics / Q000378:metabolism*; D013788:Thalamus / Q000033:anatomy & histology / 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; C120997:NR2A NMDA receptor; C121001:NR2B NMDA receptor; C432823:NR2C NMDA receptor; C464436:NR2D NMDA receptor; D009419:Nerve Tissue Proteins; D016900:Neurofilament Proteins; D009479:Neuropeptides; D009687:Nuclear Proteins; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; C044882:neurofilament protein L; C033652:postsynaptic density proteins