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The Journal of Neuroscience, November 11, 2009, 29(45):14177-14184; doi:10.1523/JNEUROSCI.3238-09.2009

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Neurobiology of Disease
NOS2 Gene Deficiency Protects from Sepsis-Induced Long-Term Cognitive Deficits

Marc Weberpals,¹ Michael Hermes,¹ S. Hermann,² Markus P. Kummer,¹ Dick Terwel,¹ Alexander Semmler,¹ Meike Berger,³ Michael Schäfers,⁴ and Michael T. Heneka¹

¹Department of Neurology, University of Bonn, 53127 Bonn, Germany, and ²Departments of Nuclear Medicine and ³Physiology I and ⁴European Institute of Molecular Imaging, University of Münster, 48149 Münster, Germany

Correspondence should be addressed to Dr. Michael T. Heneka, Department of Neurology, Clinical Neuroscience, Sigmund-Freud-Strasse 33, 53127 Bonn, Germany. Email: michael.heneka{at}ukb.uni-bonn.de

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 ¹⁸F-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.

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Received July 8, 2009; revised Sept. 16, 2009; accepted Sept. 17, 2009.

Correspondence should be addressed to Dr. Michael T. Heneka, Department of Neurology, Clinical Neuroscience, Sigmund-Freud-Strasse 33, 53127 Bonn, Germany. Email: michael.heneka{at}ukb.uni-bonn.de

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