Glutamate receptor subtype expression in human postmortem brain tissue from schizophrenics and alcohol abusers

Abstract

Antibodies to functional AMPA/kainate (GluR1, GluR2, GluR3), and kainate binding sites (GluR5–7) were used as probes to characterize and quantitate glutamatergic receptor subtypes in human post-mortem brain tissue from schizophrenic subjects and non-psychotic control subjects, which included normal controls and subjects with a previous history of alcohol abuse. Crude membrane fractions from human hippocampi and cingulate cortices were fractionated by SDS-PAGE, electrotransferred to nitrocellulose, and probed for the various glutamate receptor subytpes. Western blots were developed with chemilluminescence and the images analyzed by densitometry. Significant reductions were observed in the hippocampal immunoreactivity of both GluR2 and GluR3 AMPA/kainate receptor subtypes in schizophrenic subjects compared to the entire group of non-psychotic control subjects. No significant changes were observed in schizophrenic hippocampal GluR1 and GluR5 receptor subtypes or in levels of the structural control proteins, NCAM and tau. Significant increases were observed for GluR2 and GluR3 in the hippocampi of subjects with alcohol abuse histories when compared to the non-psychotic normal control group. When subjects with alcohol abuse histories were removed from the non-psychotic control pool, schizophrenics were no longer statistically different from the remaining normal controls. An analysis of GluR2 and GluR3 immunoreactivity in the cingulate cortex revealed no changes in these receptor subtypes among any of the groups. No alterations were observed in the immunoreactivity of these various proteins due to confounding factors such as age, sex, postmortem interval, or smoking history, except in the cingulate cortex were GluR3 receptor subtype levels were significantly reduced in the brains of smokers. These results generally do not support a role for the non-NMDA type glutamatergic receptors in schizophrenia. However, the role of chronic ethanol exposure on the human brain needs to be further investigated, and underscores the importance of defined control tissue for human postmortem studies.