Research Article: Chronic Treatment with a Promnesiant GABA-A α5-Selective Inverse Agonist Increases Immediate Early Genes Expression during Memory Processing in Mice and Rectifies Their Expression Levels in a Down Syndrome Mouse Model

Date Published: October 19, 2011

Publisher: Hindawi Publishing Corporation

Author(s): J. Braudeau, L. Dauphinot, A. Duchon, A. Loistron, R. H. Dodd, Y. Hérault, B. Delatour, M. C. Potier.


Decrease of GABAergic transmission has been proposed to improve memory functions. Indeed, inverse agonists selective for α5 GABA-A-benzodiazepine receptors (α5IA) have promnesiant activity. Interestingly, we have recently shown that α5IA can rescue cognitive deficits in Ts65Dn mice, a Down syndrome mouse model with altered GABAergic transmission. Here, we studied the impact of chronic treatment with α5IA 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 with α5IA increased IEGs expression, particularly of c-Fos and Arc genes. In Ts65Dn mice, deficits of IEGs activation were completely rescued after treatment with α5IA. In addition, normalization of Sod1 overexpression in Ts65Dn mice after α5IA treatment was observed. IEG expression regulation after α5IA treatment following behavioral stimulation could be a contributing factor for both the general promnesiant activity of α5IA and its rescuing effect in Ts65Dn mice alongside signaling cascades that are critical for memory consolidation and cognition.

Partial Text

Down syndrome (DS) affects 0.45% of human conceptions [1] and is the first cause of mental retardation. This disorder is induced by total or partial trisomy of human chromosome 21 (HSA21) that delays both physical and mental development of affected children. In particular, cognitive skills, including learning and memory functions, are severely impaired in DS subjects.

We have previously shown that treatment with α5IA alleviates learning and memory deficits of Ts65Dn mice [35] We also demonstrated that α5IA increased the expression of the IEG product Fos in specific brain regions involved in learning and memory following cognitive stimulation. Importantly, following α5IA administration, both genotypes were observed to display significant and comparable Fos induction. This potentiation of brain activity might therefore be the substratum of the general promnesiant effects of α5IA independently of the disease status. In order to gain more insight into mechanisms of the general promnesiant effects as well as the rescuing effects in Ts65Dn mice, we studied gene expression regulation networks in mice trained in the MWM task. During this continuous training episode, mice received daily injections of α5IA (5 mg/kg) for a total of 12 days. Gene expression was then measured using DNA microarrays from hippocampal RNA extracts obtained 30 min after the last training session.

We have identified genomic changes related to chronic treatment with α5IA, an α5-selective GABA-A receptor inverse agonist. Under physiological conditions in which α5IA has been shown to be promnesiant, increase of IEGs activation has been observed and in particular of c-Fos and Arc genes. This increase of activation could allow a more efficient storage of information during memory process.




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