Density and pharmacology of α5 subunit-containing GABA A receptors are preserved in hippocampus of Alzheimer’s disease patients

Abstract

The anatomical localization and pharmacology of α5 subunit-containing GABA type-A receptors in the human hippocampal formation of Alzheimer’s disease patients were studied with an α5 receptor selective ligand, [ 3H]L-655,708 and compared to age-matched human controls. Autoradiographic analyses revealed a heterogeneous distribution of [ 3H]L-655,708 binding sites in CA1–CA3 areas with high levels in stratum oriens, stratum pyramidale and stratum radiatum contrasting with low levels in stratum lacunosum. The highest quantity of α5 receptors was found in the molecular layer of the dentate gyrus. This pattern of expression was identical in both hippocampus from control and Alzheimer’s disease subjects. Quantitative studies demonstrated that the number of [ 3H]L-655,708 binding sites is well preserved in Alzheimer’s disease with only a moderate reduction (25–30%) in the CA1 subfield and entorhinal cortex. Furthermore, saturation and competition experiments with [ 3H]L-655,708 and representative benzodiazepine site ligands revealed that α5 receptors in Alzheimer’s hippocampus have an α5β2/3γ2 pharmacology and structure as in control human brain. Overall, the data reported here provide evidence for a specific expression and relative sparing of α5 subunit-containing γ-aminobutyric acid type-A receptors in the hippocampus of Alzheimer’s patients.