Improvement of Cognitive Functions and Neurotrophic Effects Across Animal Models Mediated by A5-GABAA Receptor Positive Allosteric Modulation

Reduced GABA/somatostatin (SST) signaling is reported in psychiatric, stress-related, and neurodegenerative disorders. SST+ interneurons within cortex and hippocampus inhibit the dendrites of excitatory neurons, largely through α5-containing GABAA receptors (α5-GABAAR). We showed that an α5-positive allosteric modulator (α5-PAM, GL-II-73) alleviates working memory deficits and reverses neuronal atrophy in old mice. We then investigated the behavioral and neurotrophic effects of this α5-PAM in animal models of aging, chronic stress, β-amyloid load, and tauopathy.