Central Administration of Lipopolysaccharide Induces Depressive-like Behavior in Vivo and Activates Brain Indoleamine 2,3 Dioxygenase In Murine Organotypic Hippocampal Slice Cultures

Background: Transient stimulation of the innate immune system by an intraperitoneal injection of lipopolysaccharide (LPS) activates peripheral and central expression of the tryptophan degrading enzyme indoleamine 2,3 dioxygenase (IDO) which mediates depressive-like behavior. It is unknown whether direct activation of the brain with LPS is sufficient to activate IDO and induce depressive-like behavior. Methods: Sickness and depressive-like behavior in C57BL/6J mice were assessed by social exploration and the forced swim test, respectively. Expression of cytokines and IDO mRNA was measured by real-time RT-PCR and cytokine protein was measured by enzyme-linked immunosorbent assays (ELISAs). Enzymatic activity of IDO was estimated as the amount of kynurenine produced from tryptophan as determined by high pressure liquid chromatography (HPLC) with electrochemical detection. Results: Intracerebroventricular (i.c.v.) administration of LPS (100 ng) increased steady-state transcripts of TNFa, IL-6 and the inducible isoform of nitric oxide synthase (iNOS) in the hippocampus in the absence of any change in IFNg mRNA. LPS also increased IDO expression and induced depressive-like behavior, as measured by increased duration of immobility in the forced swim test. The regulation of IDO expression was investigated using in situ organotypic hippocampal slice cultures (OHSCs) derived from brains of newborn C57BL/6J mice. In accordance with the in vivo data, addition of LPS (10 ng/ml) to the medium of OHSCs induced steady-state expression of mRNA transcripts for IDO that peaked at 6 h and translated into increased IDO enzymatic activity within 8 h postLPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFa and IL-6 protein and activation of iNOS while IFNg expression was undetectable. Conclusion: These data establish that activation of the innate immune system in the brain is sufficient to activate IDO and induce depressive-like behavior in the absence of detectable IFNg. Targeting IDO itself may provide a novel therapy for inflammation-associated depression.