A relatively frequent complication after major surgery in elderly patients is the development of postoperative cognitive dysfunction (POCD), which can persist for several days to weeks, and in rare instances even months postoperatively. In patients >60 years of age, 26% display signs of POCD after 1 week, and 10% after 3 months, compared to 3% in controls at both time points. POCD was found to be associated with increased dependency on social transfer payments, increased risk of leaving the labor market prematurely and increased mortality. The molecular and cellular mechanisms underlying POCD are unknown, as is the reason why POCD occurs more frequently in elderly patients than in younger patients. As POCD increases with age, age- related cognitive dysfunction likely represents a risk factor. It has been shown in rodents that loss of somatostatin-positive interneurons in the dentate gyrus (DG) hilus results in hyperexcitability of DG and CA3 and is associated with age-related cognitive dysfunction. However, a cause-effect relationship between loss of somatostatin-positive interneurons in the DG hilus and cognitive dysfunction has not been demonstrated so far. We therefore want to chemogenetically inhibit and genetically ablate these neurons to demonstrate that these changes are sufficient to elicit cognitive dysfunction. Moreover, we want to pharmacologically reverse these deficits and identify the molecular and cellular basis for this reversal. It has been reported that in aged rats but not in young rats a GABAA receptor ?5-positive allosteric modulator (?5-PAM) improves cognitive function, which is in line with an ?5-PAM reducing the hyperexcitability of DG and CA3 of the hippocampus in aged rats. It has also been reported that chronic intermittent propofol improves age-related cognitive dysfunction, but the molecular and cellular substrates of this action have not been identified. We want to test the hypothesis that this action of propofol is mediated by a sustained increase in expression of ?5-containing GABAA receptors on the cell surface. We also want to identify the neuronal cell population expressing the ?5-containing GABAA receptors that mediate this improvement of cognition. Furthermore, we want to test whether chemogenetic inhibition of somatostatin-positive interneurons in the DG hilus of young adult mice is sufficient to elicit the cognitive-enhancing effect of chronic intermittent propofol. Finally, we will study whether postoperative (i.e., post laparotomy) impairment of cognitive function can be prevented or reduced by chronic intermittent propofol or a GABAA receptor ?5-PAM. In summary, we will study molecular and cellular mechanisms underlying age- related postoperative cognitive dysfunction and its reversal. The proposed studies are expected to provide an avenue for the development of strategies to prevent and/or treat POCD in elderly patients. Future clinical trials could use chronic intermittent propofol or potentially ?5-PAMs, such as novel ?5-PAMs that are currently being developed for the indication of mild cognitive impairment due to Alzheimer's disease in humans in a project funded by the NIH Blueprint Neurotherapeutics Network (1UH2NS101856-01).
In an aging population, surgeries are performed on increasingly older patients, and approximately a quarter of patients >60 years of age develop postoperative cognitive dysfunction (POCD) after major surgery, which has been linked to impaired performance of activities of daily living, premature departure from the labor market and increased mortality, and is therefore of significant concern. We propose to study a cellular mechanism underlying age-related cognitive dysfunction, which may represent a risk factor for POCD, and molecular and cellular mechanisms of the reversal of this dysfunction by chronic intermittent administration of low doses of propofol, in particular the role of ?5-containing GABAA receptors on distinct hipppocampal cell types in this process. Finally, we will evaluate chronic intermittent propofol and an ?5-GABAA receptor positive allosteric modulator for prevention and/or amelioration of postoperative cognitive dysfunction and thus provide a framework for future preventative or therapeutic interventions addressing POCD in humans.
