Dysfunction of EAAT3 Enhances LPS-Induced Postoperative Cognitive Dysfunction

Background: Studies have shown that excitatory amino acid transporter 3 (EAAT3) function inhibition is related to several neurodegenerative diseases. Our previous studies also found that the EAAT3 function is intimately linked to learning and memory. In this study, we examined the role of EAAT3 in postoperative cognitive dysfunction (POCD) and explored the potential benefit of riluzole against POCD. Methods: We performed mutation analysis of SLC1A1 (encoding EAAT3) gene exons in patients of different age groups and measured EAAT3 protein expression in hippocampus of mice at different ages. Next, we established a recombinant adeno-associated viral (rAAV)-mediated shRNA to knockdown EAAT3 expression in the hippocampus of adult male mice. And then the mice received 2μg of lipopolysaccharide (LPS) intracerebroventricular microinjection to construct the POCD model. In addition, we intraperitoneally injected 4mg/kg of riluzole 2 days before LPS microinjection for consecutive 3 days in elderly male mice. Cognitive function was assessed using a Morris water maze 24h after LPS microinjection. Animal behavioral tests, as well as pathological and biochemical assays, were performed to clarify the role of EAAT3 function in POCD and evaluate the effect of activation of EAAT3 function by riluzole. Results: We found that point mutation of SLC1A1 gene exon in elderly patients was significantly different from children and adult people, and expression of EAAT3 was significantly decreased in old mice. And EAAT3 knockdown in hippocampus aggravated LPS-induced learning and memory deficits in adult male mice, and LPS significantly inhibited hippocampal EAAT3 membrane protein expression and GluA1 protein phosphorylation level in adult male mice. Moreover, riluzole pretreatment significantly increased hippocampal EAAT3 membrane protein expression and ameliorated LPS-induced cognitive impairment in old male mice. Conclusions: Our results demonstrated that the dysfunction of EAAT3 is an important risk factor for POCD susceptibility and riluzole may be a promising strategy for prevention and treating of POCD in the elderly people.