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

Abstract

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 α5-subtype (α5IA). We demonstrate that α5IA 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, α5IA enhances learning-evoked immediate early gene products in specific brain regions involved in cognition. Importantly, acute and chronic treatments with α5IA do not induce any convulsant or anxiogenic effects that are associated with GABA-A antagonists or non-selective inverse agonists of the GABA-A-benzodiazepine receptors. Finally, chronic treatment with α5IA did not induce histological alterations in the brain, liver and kidney of mice. Our results suggest that non-convulsant α5-selective GABA-A inverse agonists could improve learning and memory deficits in DS individuals.

Antidepressant effects of an inverse agonist selective for α5 GABA-A receptors in the rat forced swim test

“…Our data suggest that negative modulation at GABA-A receptors containing the α5 subunit might have produced the antidepressant effects in rats and that these effects were not confounded by locomotor infl uences. Recent animal studies with the inverse agonist selective for α5 GABA-A receptors found improved learning and memory function in models of cognitive defect, suggesting distinctive roles of different subunits [25]. The antidepressant and memory-enhancing effects are in agreement with observations that low mood is frequently combined with anxiety and cognitive impairment [26].…”

Tonic inhibition in dentate gyrus impairs long-term potentiation and memory in an Alzheimer’s disease model

“…The α5-GABA A -Rs are known to be involved in learning and memory due to their specific localization in the hippocampus 46–48 . GABA inhibition, including tonic inhibition mediated by α5-GABA A -Rs, has been reported to affect the induction and maintenance of LTP 49–52 .…”

Selective Modulators of α₅-Containing GABA_A Receptors and their Therapeutic Significance

“…As an alternative, since α 5 GABA A Rs are well documented to be involved in cognition, it was thought that negative modulators targeting these receptors may reverse the cognitive dysfunction associated with this syndrome. The cognitive ability of Ts65Dn mice in both novel object recognition and Morris water maze tasks was indeed rescued by intraperitoneal injection of the inhibitor, α 5 IA [73]. The same compound was also reported to restore the expression of immediate early genes, namely the c-Fos…”