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.

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.

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

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.

Cre/loxP-mediated chromosome engineering of the mouse genome.

Together with numerous other genome modifications, chromosome engineering offers a very powerful tool to accelerate the functional analysis of the mammalian genome. The technology, based on the Cre/loxP system, is used more and more in the scientific community in order to generate new chromosomes carrying deletions, duplications, inversions and translocations in targeted regions of interest. In this review, we will present the basic principle of the technique either in vivo or in vitro and we will briefly describe some applications to provide highly valuable genetic tools, to decipher the mammalian genome organisation and to analyze human diseases in the mouse.

Optic flow is used to control human walking.

How is human locomotion visually controlled? Fifty years ago, it was proposed that we steer to a goal using optic flow, the pattern of motion at the eye that specifies the direction of locomotion. However, we might also simply walk in the perceived direction of a goal. These two hypotheses normally predict the same behavior, but we tested them in an immersive virtual environment by displacing the optic flow from the direction of walking, violating the laws of optics. We found that people walked in the visual direction of a lone target, but increasingly relied on optic flow as it was added to the display. The visual control law for steering toward a goal is a linear combination of these two variables weighted by the magnitude of flow, thereby allowing humans to have robust locomotor control under varying environmental conditions.

The human visual system averages speed information.

It has been known for many years that human observers are unable to detect modest accelerations and decelerations in moving visual stimuli. We find that human observers can integrate speeds over many dots, moving at different speeds, producing a global speed percept analogous to the global direction percept first reported by Williams, D. W. and Sekuler, R. (1984, Vision Research, 24, 55-62). We measured speed discrimination for random dot stimuli which contained many different speeds. Our results show that observers always base their discrimination on the mean speed of the stimulus; changes in other stimulus characteristics (e.g. mode) are not detected. Moreover, discrimination thresholds for the global mean speed derived from many different speeds are comparable to those obtained with stimuli in which all dots move at the same speed suggesting that the internal noise associated with the encoding of speed information is quite high.

Oxygen free radical involvement in ischemia and reperfusion injury to brain.

Evidence is presented which implicates increased oxygen free radicals during ischemia reperfusion of gerbil brain. Salicylate, which reacts with hydroxyl free radicals to yield dihydroxybenzoic acid (DHBA), was used as an in vivo trap. Brain ischemia for at least 5 min followed by reperfusion yielded significantly increased brain DHBA. Without reperfusion or with only 2 min of ischemia and then reperfusion, the production of DHBA was not increased. Increased levels of DHBA in brain correlated with ischemia reperfusion-mediated behavioral modification of gerbils, but salicylate administration did not protect against the behavior changes.