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.
Highlights
Down syndrome (DS) is the consequence of trisomy 21, the most common genetic cause of mental retardation (1/800 live births), and is characterized by varying degrees of cognitive impairments (Sherman et al, 2007)
As a prerequisite we checked that the level of expression of the Gabra5 gene encoding the a5 Gamma-aminobutyric acid (GABA)-A subunit was unchanged in the hippocampus of Ts65Dn mice as compared with euploids (t14 1⁄4 0.40, p 1⁄4 0.69; data not shown) confirming the presence of the pharmacological target in Ts65Dn mice
We determined the optimal dose of a5IA that induced clear promnesic effects in mice trained in the delayed matching-to-place task (DMTP) version of the Morris water maze task (MWM) task (Figure 1(a))
Summary
Down syndrome (DS) is the consequence of trisomy 21, the most common genetic cause of mental retardation (1/800 live births), and is characterized by varying degrees of cognitive impairments (Sherman et al, 2007). Advances in teaching methods and educational mainstreaming have proven to be beneficial to people with DS, but are clearly not sufficient to counteract all cognitive deficits (Wishart et al, 2007). Since these individuals have a life expectancy of 55 years and often survive their parents, treatments aimed at enhancing cognitive skills to provide higher autonomy are long-awaited. Treatment of DS mouse models with non-competitive GABA-A
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