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Ionotropic Glutamate Receptor Binding and Subunit mRNA Expression in Thalamic Nuclei in Schizophrenia

OBJECTIVE: Both thalamic and glutamatergic dysfunction have been implicated in the pathophysiology of schizophrenia. The authors examined ionotropic glutamate receptor expression in postmortem samples from patients with schizophrenia and comparison subjects, using the hypothesis that glutamate receptor expression differs in limbic nuclei of the thalamus in schizophrenia. METHOD: N-Methyl-D-aspartate (NMDA), AMPA, and kainate receptor expression was determined in six thalamic nuclei from 12 subjects with DSM-III-R diagnoses of schizophrenia and eight psychiatrically normal individuals. The authors used in situ hybridization to determine NMDAR1, NMDAR2A–NMDAR2D, gluR1–gluR7, KA1, and KA2 subunit mRNA levels and receptor autoradiography to determine binding to glutamate binding sites of the three receptor subtypes and to the glycine, polyamine, and ion channel binding sites of the NMDA receptor. RESULTS: Glutamate receptor expression was lower at both transcriptional (NMDAR1, NMDAR2B, NMDAR2C, gluR1, gluR3, and KA2 subunit mRNAs) and posttranscriptional ([³H]ifenprodil and [³H]MDL105,519 binding to polyamine and glycine sites of the NMDA receptor) levels in the thalamus in patients with schizophrenia than in comparison subjects, but differences were most prominent in nuclei with reciprocal projections to limbic regions. CONCLUSIONS: Abnormalities in NMDA, AMPA, and kainate receptor expression in limbic thalamus are suggestive of the NMDA receptor hypoactivity hypothesis of schizophrenia and are consistent with diminished glutamatergic activity in the thalamus in schizophrenia. Alternatively, these results could suggest abnormal glutamatergic innervation in afferent and/or efferent regions, which are limbic structures that have been implicated in this illness. These results may provide a neurochemical anatomical substrate for antipsychotic therapies targeting ionotropic glutamate receptors.

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