Mechanisms of Neuronal Dysfunction in Sepsis-induced Cognitive Impairment

Abstract

Sepsis is a severe and frequent disease in modern intensive medicine. Sepsis does not only present with a mortality rate of 30% of all patients, but survivors often show long lasting cognitive deficits, loss of independency and reduced quality of life. However, the mechanisms of sepsis-induced cognitive impairments remain incompletely understood so far. To understand the mechanisms of cognitive decline in sepsis survivors, the possible involvement of the brain’s primary immune cells, microglia, was investigated in this project. In particular, to investigate if and how microglia contribute to synapse loss acutely and long-term after sepsis, different phagocytosis-deficient mice strains were analyzed for synapse number and phagocytosed synapse number. To model sepsis, female mice were injected on two consecutive days with either 1.5 mg/kg body weight lipopolysaccharide (LPS), a bacterial cell wall component that induces strong inflammatory responses. At different timepoints (1 day, 3 days, 7 days or 2 months) tissue was then analysed. Acutely after LPS-injections, quantification of phagocytic proteins showed a sharp increase in complement protein 3 in the brain. Consistently, immunohistochemical analysis revealed, that functional synapse number was strongly reduced and that the percentage of phagocytosed synapses was increased by LPS treatment. Interestingly, mice deficient in phagocytic signaling proteins (Mfge8 -/-, Cd11b-/-) showed no reduction in functional synapse number and no increase in phagocytosis of functional synapses after LPS-injections. Therefore, microglial phagocytosis leads to synapse loss in a mouse model of sepsis and may contribute to long-term cognitive deficits in sepsis survivors. Inhibition of specific microglial pathways could therefore be a promising new strategy to prevent long-term cognitive deficits in sepsis survivors.