System x(c)(−) in microglia is a novel therapeutic target for post-septic neurological and psychiatric illness

Post-septic neurological and psychiatric illness (PSNPI) including dementia and depression may be observed after sepsis. However, the etiology of PSNPI and therapeutic treatment of PSNPI are unclear. We show that glutamate produced from microglia through the activity of system x(c)(−) plays a role in PSNPI. We established a mouse model of PSNPI by lipopolysaccharide (LPS) treatment that shows a disturbance of short/working memory and depression-like hypoactivity. Glutamate receptor antagonists (MK801 and DNQX) reduced these phenotypes, and isolated microglia from LPS-treated mice released abundant glutamate. We identified system x(c)(−) as a source of the extracellular glutamate. xCT, a component of system x(c)(−), was induced and expressed in microglia after LPS treatment. In xCT knockout mice, PSNPI were decreased compared to those in wildtype mice. Moreover, TNF-α and IL-1β expression in wildtype mice was increased after LPS treatment, but inhibited in xCT knockout mice. Thus, system x(c)(−) in microglia may be a therapeutic target for PSNPI. The administration of sulfasalazine, an inhibitor of xCT, in symptomatic and post-symptomatic mice improved PSNPI. Our results suggest that glutamate released from microglia through system x(c)(−) plays a critical role in the manifestations of PSNPI and that system x(c)(−) may be a therapeutic target for PSNPI.