Antisense oligonucleotide to GABA A receptor γ2 subunit induces loss of neurones in rat hippocampus

Abstract

The binding site for 1,4-benzodiazepines in the brain is part of the hetero-oligomeric γ-aminobutyric acid (GABA) A receptor complex which regulates a chloride ion channel. The presence of the γ2 subunit in the complex is necessary for the binding of benzodiazepines to their binding site. This study demonstrates a reduction of benzodiazepine receptor radioligand binding by 43% compared to control following infusion of phosphorothioate antisense oligodeoxynucleotide to γ2 subunit into rat hippocampus. Reduction of benzodiazepine binding sites, was paralleled by a decrease in [ 35S]tert-butyl-bicyclo-phosphorothionate ([ 35S]TBPS) binding (51%) and [ 3H]muscimol binding (37%), indicating a reduction in the number of GABA A receptors. Changed macroscopic appearance, reduced protein content and severe loss of neurones in anti sense-treated hippocampi suggests that the reduced formation of GABA A receptors leads to neuronal cell death.