GABA is the main inhibitory neurotransmitter in the mammalian brain and its fast actions are mainly mediated by GABA-gated ion channels, the GABA-A receptors. GABA is supposed to fully activate all GABAA receptor subtypes. However, it is known that there are GABA-A receptors, in which GABA has atypically low efficacy e.g. to displace the binding of an ionophore ligand [35-S]TBPS from certain regions of the brain (Sinkkonen et al., Mol Brain Res. 86:168-78, 2001). We have used a transgenic Thy1alpha6 mouse line with forebrain expression of GABA-A receptor alpha6 subunits under the Thy1 promoter to reveal atypically low GABA efficacy especially in the CA1 region of the hippocampus, which has ectopic alpha6beta subtype expression. In this brain region of the mutant mice, the full agonist action of gaboxadol was inhibited by GABA. Similar interaction was observed also in the thalamus and cerebellar granule cell layer of both the mutant and wild-type mice. The data indicate that there are populations of GABA-A receptors, in which GABA seems to be only a partial agonist, and by which potent sedative actions of gaboxadol might be mediated.

Supported by the Academy of Finland.