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 TNFalpha, IL-6 and the inducible isoform of nitric oxide synthase (iNOS) in the hippocampus in the absence of any change in IFN gamma 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 post-LPS. This activation of IDO by direct application of LPS was preceded by synthesis and secretion of TNFalpha and IL-6 protein and activation of iNOS while IFN gamma expression was undetectable.


CONCLUSIONS
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 IFN gamma. Targeting IDO itself may provide a novel therapy for inflammation-associated depression.
Fu
Xin
X
Integrative Immunology and Behavior Program, Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Zunich
Samantha M
SM
O'Connor
Jason C
JC
Kavelaars
Annemieke
A
Dantzer
Robert
R
Kelley
Keith W
KW
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000201:enzymology / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003863:Depression / Q000139:chemically induced* / Q000276:immunology / Q000503:physiopathology; D004789:Enzyme Activation; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects* / Q000201:enzymology* / Q000276:immunology; D007113:Immunity, Innate / Q000276:immunology*; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000235:genetics / Q000378:metabolism*; D007276:Injections, Intraventricular; D007371:Interferon-gamma / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism; D046509:Tissue Culture Techniques
D016207:Cytokines; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D008070:Lipopolysaccharides; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse