Enhanced behavioral sensitivity to the competitive GABA agonist, gaboxadol, in transgenic mice over‐expressing hippocampal extrasynaptic α6β GABAAreceptors

Open Access
Publisher Website
Google Scholar
Abstract
The behavioral and functional significance of the extrasynaptic inhibitory GABAAreceptors in the brain is still poorly known. We used a transgenic mouse line expressing the GABAAreceptor α6 subunit gene in the forebrain under the Thy‐1.2 promoter (Thy1α6) mice ectopically expressing α6 subunits especially in the hippocampus to study how extrasynaptically enriched αβ(γ2)‐type receptors alter animal behavior and receptor responses. In these mice extrasynaptic α6β receptors make up about 10% of the hippocampal GABAAreceptors resulting in imbalance between synaptic and extrasynaptic inhibition. The synthetic GABA‐site competitive agonist gaboxadol (4,5,6,7‐tetrahydroisoxazolo[5,4‐c]pyridin‐3‐ol; 3 mg/kg) induced remarkable anxiolytic‐like response in the light : dark exploration and elevated plus‐maze tests in Thy1α6 mice, while being almost inactive in wild‐type mice. The transgenic mice also lost quicker and for longer time their righting reflex after 25 mg/kg gaboxadol than wild‐type mice. In hippocampal sections of Thy1α6 mice, the α6β receptors could be visualized autoradiographically by interactions between gaboxadol and GABA via [35S]TBPS binding to the GABAAreceptor ionophore. Gaboxadol inhibition of the binding could be partially prevented by GABA. Electrophysiology of recombinant GABAAreceptors revealed that GABA was a partial agonist at α6β3 and α6β3δ receptors, but a full agonist at α6β3γ2 receptors when compared with gaboxadol. The results suggest strong behavioral effects via selective pharmacological activation of enriched extrasynaptic αβ GABAAreceptors, and the mouse model represents an example of the functional consequences of altered balance between extrasynaptic and synaptic inhibition.