Postoperative Neurocognitive Disorder - Strategies for Prevention or Reversal Based on Molecular ad Cellular Mechanisms - 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 α5- containing GABAA receptors (α5-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 α5-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 α5-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 α5-GABAARs (with chronic intermittent propofol) and positive allosteric modulation of α5-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 α5-GABAARs can attenuate surgery-induced inflammation. We plan to examine the exact timing of the effects of such an increased functional activity of the α5-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 α5 “deficit” with aging. Transcriptomic studies will reveal whether increased availabiliy of α5-GABAARs on cell surface membranes or positive allosteric modulation of α5-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 α5-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 α5-GABAARs in different principal neurons and interneuronal cell types and on microglia cells we expect to see a contribution of α5-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 α5-GABAARs in elderly patients undergoing surgery and anesthesia. Positive allosteric modulators of α5-GABAARs are currently being developed by others, and once such compounds become available for experimental use in humans, our proposed studies provide a fundamental science framework supporting clinical studies for poNCD.
