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 NR₁ subunit is expressed as one of eight isoforms due to the alternative splicing of exons 5, 21, and 22. Alternative splicing of NR₁ subunits modulates receptor function by influencing the association of NR₁ 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 NR₁ and NR_2C are abnormally expressed in the thalamus in schizophrenia. They hypothesized that this reduction is associated with specific NR₁ isoforms and that NMDA receptor-related postsynaptic density proteins are abnormally expressed. METHOD: Using in situ hybridization, the authors examined expression of the transcripts encoding NR₁ isoforms containing exons 5, 21, or 22, and the NMDA receptor-related postsynaptic density proteins NF-L, PSD93, PSD95, and SAP102. RESULTS: Reduced NR₁ 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.