Changes in hippocampal GABA A receptor subunit composition in bipolar 1 disorder

Abstract

Postmortem CNS studies have suggested an uncoupling of the γ-aminobutyric acid (GABA) and benzodiazepine binding sites on the hippocampal GABA A receptor in schizophrenia. The GABA A receptor is an assembly of discrete subunits that form a ligand-gated ion channel, the binding characteristics of which are defined by receptor subunit composition. Thus, a likely explanation for an uncoupling between the GABA and benzodiazepine binding sites on the GABA A receptor would be a change in receptor subunit composition. To test this hypothesis we measured the density of GABA ([ 3H]muscimol) and benzodiazepine ([ 3H]flumazenil) binding sites on the GABA A receptor in hippocampi, obtained postmortem, from schizophrenic, bipolar I disorder and control subjects. In addition, we measured the amount of [ 3H]flumazenil binding that could be displaced with zolpidem and clonazepam. Levels of both [ 3H]muscimol and [ 3H]flumazenil binding were significantly decreased in part of the CA2 from subjects with schizophrenia; the decrease in [ 3H]flumazenil being due to decreases in both zolpidem-sensitive and -insensitive radioligand binding. There were complex regionally specific changes in [ 3H]muscimol binding in the hippocampus from subjects with bipolar I disorder but there were no significant changes in the overall levels of [ 3H]flumazenil binding. There were significant decreases in zolpidem-sensitive and increases in zolpidem-insensitive [ 3H]flumazenil binding in most regions of the sections of the hippocampal formation studied in bipolar I disorder. Unlike [ 3H]flumazenil, zolpidem does not bind to the α5 subunit of the GABA A receptor; therefore, we postulate that there is an increase in GABA A receptors containing α5 subunit in the hippocampus from subjects with bipolar I disorder.