NOS2 gene deficiency protects from sepsis-induced long-term cognitive deficits.
To date, long-term consequences of septic encephalopathy on cerebral metabolism, cognition, learning, and memory capabilities and factors involved are poorly understood. In this study, we used a murine sepsis model to demonstrate that bacterial lipopolysaccharide (LPS) causes long-term cognitive deficits in mice. Two months after LPS treatment, wild-type mice committed more working and reference memory errors than controls. The behavioral impairment was independent of the cerebral glucose uptake as evidenced by (18)F-Fluordeoxyglucose small animal positron emission tomography. In contrast, mice deficient for the inducible nitric oxide synthase gene (NOS2-/-) did not show any cognitive changes when challenged with LPS. Immunohistochemical analysis demonstrated that LPS did not lead to neuronal cell death but caused sustained microglial activation in wild-type as compared to NOS2-/- mice. Expression analysis showed that LPS-treated NOS2-/- mice had lower brain mRNA levels for proinflammatory factors compared with wild-type mice. Expression analysis demonstrated distinct changes in the content of synaptic proteins in wild-type mice, which were not observed in the NOS2-/- mice. Together, this data set outlines the importance of the NOS2 activation for long-term cerebral changes after severe sepsis.
Weberpals
Marc
M
Department of Neurology, University of Bonn, 53127 Bonn, Germany.
Hermes
Michael
M
Hermann
S
S
Kummer
Markus P
MP
Terwel
Dick
D
Semmler
Alexander
A
Berger
Meike
M
Schäfers
Michael
M
Heneka
Michael T
MT
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects; D003072:Cognition Disorders / Q000209:etiology* / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D008070:Lipopolysaccharides; D018782:Maze Learning / Q000502:physiology; D008570:Memory, Short-Term / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011877:Radionuclide Imaging; D018805:Sepsis / Q000139:chemically induced / Q000150:complications* / Q000503:physiopathology*; D013569:Synapses / Q000502:physiology
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse; D005947:Glucose