Seminar – Etienne Sibille, Ph.D.

Inhibitory GABAergic Deficits and Cognition in Depression and During Aging: Mechanisms and Therapeutic Targeting

 

Changes in the brain balance between chemical excitation and inhibition are frequently described in neuropsychiatric disorders and during aging. We have now identified cellular and molecular changes that correspond to this imbalance and that specifically affect GABA function, the main inhibitory neurotransmitter system in the brain. These changes were identified in human postmortem brain samples in depression and during aging. Using genetic and environmental mouse models we then showed that these pathological changes are likely causing changes in cognitive function and mood symptoms. The next step was to identify the specific molecules and brain receptors that mediate these deficits. Finally we now show that novel molecules that activate these receptors, namely the alpha5-containing GABA-A receptor, can rapidly reverse cognitive dysfunction (namely spatial working memory) induced by chronic stress in adult or importantly by aging. Specifically we show that aged mice behave as young mice in tests of working memory 30 minutes after a single dose of our novel molecules. These novel molecules have promising therapeutic and safety profiles, paving the way for their clinical development and testing in human subjects. Together our findings highlight a link between deficits in cortical microcircuits and cognition, and suggest novel therapeutic approaches for the currently untreated cognitive symptoms that are prevalent during aging and across multiple brain disorders.