iNOS gene deficiency protects from sepsis induced cognitive long-term deficits

Septic encephalopathy (SE) is caused by systemic inflammation in the absence of direct brain infection. While the acute reactions to SE have been well defined, the long-term consequences of SE on cerebral metabolism, cognition, learning and memory capabilities remain to be elucidated. Using a murine model of sepsis, we demonstrate that a single injection of lipopolysaccharide (LPS), a gramnegative bacterial cell wall component, results in long-term cognitive deficits. Two month after the initial challenge, LPS treated mice committed more working and reference memory errors than controls. These behavioural changes were accompanied by reduced cortical glucose uptake as evidenced by small animal 18F-FDG-PET studies. In contrast, mice deficient for the inducible nitric oxide synthase gene (iNOS KO), did not show any cognitive changes and revealed a normal cerebral glucose uptake when challenged with LPS using the identical protocol. LPS induced SE did not cause neuronal cell death, since serial sectioning of brains and subsequent immunohistological analysis did not detect any changes. However, further analysis of inflammatory genes showed that LPS treated iNOS KO mice had lower mRNA levels of proinflammatory cytokines and chemokines, including tumor necrosis factor alpha and interleukin 1 beta, compared to LPS challenged wild type animals, suggesting that NO is involved in the transcriptional control of these genes. Synaptosome preparations and detection of key synaptic proteins revealed distinct LPS induced changes of protein levels along with sepsis induced and NO mediated nitration and nitrosylation of tyrosine and cysteine residues. Together these data suggest that sepsis is causing long-lasting cognitive deficits, which are influenced by iNOS dependent NO generation and NO mediated alterations at the synaptic level.