Ionotropic Glutamate Receptors and Expression of N-Methyl-d-Aspartate Receptor Subunits in Subregions of Human Hippocampus: Effects of Schizophrenia

OBJECTIVE: Multiple quantifiable biologic abnormalities have been localized to the hippocampus in schizophrenia. Alterations in glutamate-mediated transmission at N-methyl-d-aspartic acid (NMDA)-sensitive receptors in hippocampus have been implicated in the pathophysiology of the illness. The authors tested the hypothesis that glutamatergic transmission within and efferent from hippocampus is altered in schizophrenia.METHOD: The authors analyzed postmortem hippocampal tissue from individuals with schizophrenia and from healthy individuals. The tissue samples had been collected by two brain tissue banks, one in Maryland and the other in Melbourne, Australia. lonotropic receptor binding for the NMDA, kainate, and ³H-amino-3-hydroxy-5-methylisoxazol-4-propionate (AMPA) receptors was quantified by using usual radioligand techniques. In situ hybridization autoradiography was used to quantify mRNA for the NMDA receptor subunits NR1, NR2A, and NR2B.RESULTS: Ligand binding to the ionotropic glutamate receptors (NMDA, kainate, and AMPA) did not differ significantly overall or in any subregion between the schizophrenia tissue and the healthy comparison tissue. The only exception was AMPA receptor binding in hippocampal subregion CA2, which was slightly but significantly less in schizophrenia. However, the level of mRNA for the NMDA receptor subunits NR1 and NR2B was significantly different between groups; in several hippocampal subregions, the level of NR1 mRNA was lower and the level of NR2B mRNA higher in schizophrenia.CONCLUSIONS: Because the NR1 subunit of the NMDA receptor is critical to full receptor activity, a reduction of NR1 in hippocampus in schizophrenia suggests a functional impairment in glutamatergic transmission at the NMDA receptor, resulting in reduced glutamatergic transmission within and possibly efferent from the hippocampus in schizophrenia. This defect could underlie a hypoglutamatergic state in regions of limbic cortex, consistent with published results from other lines of research in schizophrenia.