Chronic Treatment with a Promnesiant GABA-Aα5-Selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model

摘要

Decrease of GABAergic transmission has been proposed to improve memory functions. Indeed, inverse agonists selective forα5 GABA-A-benzodiazepine receptors (α5IA) have promnesiant activity. Interestingly, we have recently shown thatα5IA can rescue cognitive deficits in Ts65Dn mice, a Down syndrome mouse model with altered GABAergic transmission. Here, we studied the impact of chronic treatment withα5IA on gene expression in the hippocampus of Ts65Dn and control euploid mice after being trained in the Morris water maze task. In euploid mice, chronic treatment withα5IA increased IEGs expression, particularly ofc-FosandArcgenes. In Ts65Dn mice, deficits of IEGs activation were completely rescued after treatment withα5IA. In addition, normalization ofSod1overexpression in Ts65Dn mice afterα5IA treatment was observed. IEG expression regulation afterα5IA treatment following behavioral stimulation could be a contributing factor for both the general promnesiant activity ofα5IA and its rescuing effect in Ts65Dn mice alongside signaling cascades that are critical for memory consolidation and cognition.