Specific targeting of the GABA-A receptor α5 subtype by a selective inverse agonist restores cognitive deficits in Down syndrome mice

An imbalance between inhibitory and excitatory neurotransmission has been proposed to contribute to altered brain function in individuals with Down syndrome (DS). Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system and accordingly treatment with GABA-A antagonists can efficiently restore cognitive functions of Ts65Dn mice, a genetic model for DS. However, GABA-A antagonists are also convulsant which preclude their use for therapeutic intervention in DS individuals. Here, we have evaluated safer strategies to release GABAergic inhibition using a GABA-A-benzodiazepine receptor inverse agonist selective for the alpha 5-subtype (alpha 5IA). We demonstrate that alpha 5IA restores learning and memory functions of Ts65Dn mice in the novel-object recognition and in the Morris water maze tasks. Furthermore, we show that following behavioural stimulation, alpha 5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with alpha 5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or nonselective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with alpha 5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant alpha 5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals.