DECREASED EXPRESSION OF MESSENGER-RNAS ENCODING NON-NMDA GLUTAMATE RECEPTORS GLUR1 AND GLUR2 IN MEDIAL TEMPORAL-LOBE NEURONS IN SCHIZOPHRENIA

Schizophrenia is associated with a complex pattern of alterations in the glutamatergic system of the brain. Previous studies have shown a reduced density of some hippocampal non-N-methyl-D-aspartate (non-NMDA) receptors which is accompanied by a loss of encoding receptor mRNA. We have extended this work using in situ hybridization histochemistry with oligonucleotide probes specific for two non-NMDA receptor transcripts, GluR1 and GluR2, in right and left medial temporal lobe sections from 9 schizophrenics and 14 matched normal controls. Both mRNAs were found to be decreased bilaterally and to a similar degree in the hippocampal formation in schizophrenia. Analysis of autoradiograms showed a regional loss of GIuR1 and GluR2 mRNAs in dentate gyrus, CA4, CA3 and subiculum. GluR2 mRNA was also reduced in parahippocampal gyrus. These reductions ranged from 25% to 70% in terms of S-35 nCi/g tissue equivalents. Additionally we measured grain density for the mRNAs over individual pyramidal neurons in each area. GluR1 and GluR2 mRNAs were less abundant per neuron in CA4 and CA3 in schizophrenia than in controls. GluR2 mRNA was also reduced significantly in parahippocampal gyrus neurons, with an increase in the proportion of GluR1 mRNA to GluR2 mRNA in this cell population. No asymmetries in expression of GluR1 and GluR2 were found in normal or schizophrenic brains. These data further the evidence for reduced non-NMDA receptor expression in the medial temporal lobe in schizophrenia. They confirm the decrease in GluR1 mRNA and show that there are similar losses of GluR2 mRNA in the hippocampal formation. The pattern of changes in the two mRNAs suggests a common mechanism which is unknown but which may be a correlate of the neurodevelopmental abnormalities postulated to underlie the disease. The reduction of GluR2 mRNA but not GluR1 mRNA in parahippocampal gyrus neurons in schizophrenia may have functional consequences given the calcium permeability of non-NMDA receptors lacking the GluR2 subunit.