title: 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.
authors.affiliation: Centre de Recherche de l'Institut du Cerveau et de Moelle Epinière, CNRS UMR7225, INSERM UMRS 975, UPMC, Paris, France.
authors.forename: J
authors.initials: J
authors.lastname: Braudeau
authors.forename: B
authors.initials: B
authors.lastname: Delatour
authors.forename: A
authors.initials: A
authors.lastname: Duchon
authors.forename: P Lopes
authors.initials: PL
authors.lastname: Pereira
authors.forename: L
authors.initials: L
authors.lastname: Dauphinot
authors.forename: F
authors.initials: F
authors.lastname: de Chaumont
authors.forename: J-C
authors.initials: JC
authors.lastname: Olivo-Marin
authors.forename: R H
authors.initials: RH
authors.lastname: Dodd
authors.forename: Y
authors.initials: Y
authors.lastname: Hérault
authors.forename: M-C
authors.initials: MC
authors.lastname: Potier
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology; D004195:Disease Models, Animal; D004314:Down Syndrome / Q000188:drug therapy* / Q000503:physiopathology; D016503:Drug Delivery Systems; D054314:Drug Inverse Agonism; D058785:GABA-A Receptor Agonists / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008568:Memory / Q000187:drug effects; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D010793:Phthalazines / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity; D011963:Receptors, GABA-A / Q000187:drug effects* / Q000378:metabolism; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C555638:3-(5-methylisoxazol-3-yl)-6-((1-methyl-1,2,3-triazol-4-yl)methyloxy)-1,2,4-triazolo(3,4-a)phthalazine; D058785:GABA-A Receptor Agonists; C496250:Gabra5 protein, mouse; D010793:Phthalazines; D011963:Receptors, GABA-A; D014230:Triazoles