Cellular mechanisms for age-related cognitive dysfunction and its pharmacological reversal: a strategy towards prevention and treatment of postoperative cognitive deficits in elderly patients

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PROJECT SUMMARY / ABSTRACT 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 α5-positive allosteric modulator (α5-PAM) improves cognitive function, which is in line with an α5-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 α5-containing GABAA receptors on the cell surface. We also want to identify the neuronal cell population expressing the α5-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 α5-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 α5-PAMs, such as novel α5-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).