PROJECT SUMMARY / ABSTRACT Aging has long been known to be a risk factor for the development of postoperative neurocognitive disorder (poNCD), but the mechanisms underlying this observation are largely obscure. Approximately 10% of patients > 60 years of age undergoing surgery and anesthesia develop poNCD, which can be present for several months. Work by others indicates that in young adult mice several general anesthetics lead to a redistribution of 5- containing GABAA receptors (5-GABAARs) into cell surface membranes, which is associated with an impairment of cognitive function. It has been shown in mice that negative allosteric modulation of 5-GABAARs blocks the sustained memory-impairing effects of general anesthetics. This is the current “dogma” in the field. Our hypothesis is, however, that an age-related functional reduction of the 5-GABAA receptor system at least in part underlies declining cognitive functions with aging. In support of this hypothesis, we have demonstrated that in aged mice (>18 months of age) both increasing the availability of 5-GABAARs (with chronic intermittent propofol) and positive allosteric modulation of 5-GABAARs (with MP-III-022) result in cognitive improvements and an essentially complete block of surgery-induced memory impairments. We now propose to study molecular and cellular mechanisms underlying age-related cognitive decline including the mechanisms by which increased activity of 5-GABAARs can attenuate surgery-induced inflammation. We plan to examine the exact timing of the effects of such an increased functional activity of the 5-GABAARs on blocking the development of postoperative cognitive deficits to examine differential contributions of a reduction of microglial activation and of a normalization of an 5 “deficit” with aging. Transcriptomic studies will reveal whether increased availabiliy of 5-GABAARs on cell surface membranes or positive allosteric modulation of 5-GABAARs reverse at least some of the aging-related changes in gene expression and mitochondrial function. We then want to clarify the role of a specific GABAA receptor subtype on astroytes and of astrocytes in general on the distrubution of 5-GABAARs in cellular membranes, in part using calcium imaging in vivo. Finally, we want to identify cellular targets underlying the prevention or reversal of postoperative cognitive deficits in aged mice. In mice conditionally lacking 5-GABAARs in different principal neurons and interneuronal cell types and on microglia cells we expect to see a contribution of 5-GABAARs on multiple cell types to the attenuation of postoperative cognitive deficits. The involvement of the hippocampus in this process will be assessed by monitoring place cell formation and stability of the memory engram by calcium imaging in vivo. The proposed studies are envisioned to have a positive translational impact, providing a pathway for testing the positive modulation of 5-GABAARs in elderly patients undergoing sur...