108. SELECTIVE POTENTIATION OF α5-GABAA RECEPTORS CONTRIBUTES TO REDUCTION OF COGNITIVE BURDEN AND NEURONAL LOSS IN AGING MICE

Abstract Background Reduced GABA/somatostatin (SST) signaling is reported in aging as well as in psychiatric, stress-related and neurodegenerative disorders. Cortical SST+ interneurons inhibit the dendrites of excitatory neurons, largely through α5-containing GABAA receptors (α5-GABAAR). We previously showed that an α5-positive allosteric modulator (α5-PAM) alleviates working memory deficits and reverses neuronal atrophy in young mice subjected to chronic stress, and in old mice. We then started to investigate the efficacy of this α5-PAM on other cognitive domains, investigated further the neurotrophic effects looking at markers of synaptic functions, and tested the requirement of the α5-subunit in such effects, using transgenic models insensitive to α5-PAMs. Aims & Objectives The aim of this study was to demonstrate the efficacy of chronic α5-PAM administration at reducing cognitive burden in old mice, with a focus on working memory, spatial learning and memory, and cognitive flexibility, and demonstrate the requirement of α5-GABAAR in cognitive and neurotrophic effects of α5-PAM. Method Male and female C57BL6 mice (~12/group) and α5-Knock-In mice (~14/group) for which a point mutation is introduced in the binding pocket of α5-PAM, rending the α5-GABAAR insensitive to α5-PAM, were included in the study. Efficacy of 4 weeks of the α5-PAM GL-II-73 (30mg/kg, p.o) at rescuing cognitive deficits was assessed for working memory (alternation task), spatial memory (water maze), and cognitive flexibility (set-shifting), in comparison to performance from old mice receiving vehicle. Brains were then collected and either stained (Golgi-Cox; n=4brain/group; 8cell/brain) for spine density and maturation quantification in the prefrontal cortex and hippocampus (NeuroLucida), or processed for western blot assay to measure synaptic markers (PSD95, SYN1, GPHN, RDX, etc.) in the same brain regions. Results Chronic treatment reversed cognitive deficits (ps<0.01), with a strong effect on working memory. It also reversed neuronal atrophy (p<0.001 in PFC and CA1). Both procognitive and neurotrophic effects were observed only in animals with α5-GABAAR still sensitive to α5-PAM (i.e. the α5-KI mice did not benefit from the procognitive and neuronal benefits of the α5-PAM). Discussion & Conclusions Results support that selective α5-targeting of GABAA receptors overcomes aging-related cognitive deficits and detriments in neuronal morphology. These studies also demonstrate the requirement for functional and drug-sensitive α5-GABAAR in order to elicit the procognitive and neutrophic effects of α5-PAM. Altogether, these studies demonstrate that a GABAergic intervention could represent a major avenue for clinical development for patients suffering from cognitive deficits in aging, and could be of interest for other age-related disorders.