Inflammatory stimuli reduce survival of serotonergic neurons and induce neuronal expression of indoleamine 2,3-dioxygenase in rat dorsal raphe nucleus organotypic brain slices.

Abstract

Neuroinflammation results in dysregulation of serotonergic neurons in the dorsal raphe nucleus (doR) and is considered to play an important role in the pathophysiology of depression. The aim of the present study was to induce neuroinflammation in a simple doR brain slice model using lipopolysaccharide (LPS), interferon-gamma (IFNγ), beta-amyloid₁₋₄₂ or tumor necrosis factor-alpha and to explore the survival of serotonergic neurons and the expression of the tryptophan degrading enzyme indoleamine 2,3-dioxygenase (IDO). Administration of pro-inflammatory stimuli reduced survival of serotonergic neurons in doR slices and increased IDO expression. IFNγ most potently induced IDO expression, which co-localized with neurons, including serotonergic neurons, but not with microglia or astrocytes. IFNγ did not induce PI-positive staining in slices, but increased the average nuclei size of IDO-positive cells. The inflammation-induced decline did not return to control levels, when slices were withdrawn from inflammation, pointing to neurodegeneration. The growth factors BDNF or GDNF did not counteract the inflammation-induced decrease in serotonergic neurons, except for LPS-induced neuronal decline. The inflammation-induced effect was not blocked by the NMDA-receptor antagonist MK-801. Further LPS, but not IFNγ increased inflammatory markers and microglia activity. In conclusion, our data show that a range of inflammatory stimuli decline serotonergic neurons in doR slices and upregulate IDO expression. The data suggest that IDO does not contribute to serotonergic decline, but may serve as a marker of neurodegeneration. Neuroinflammation may contribute to the development of depression.

• Authors: T Hochstrasser, C Ullrich, B Sperner-Unterweger, C Humpel
• Journal: Neuroscience (Neuroscience) Vol. 184 Pg. 128-38 (Jun 16 2011) ISSN: 1873-7544 [Electronic] United States
• PMID: 21501664 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Indoleamine-Pyrrole 2,3,-Dioxygenase
• Lipopolysaccharides
• Serotonin

Topics

• Animals
• Astrocytes (drug effects, immunology, metabolism)
• Cell Survival (drug effects, immunology)
• Indoleamine-Pyrrole 2,3,-Dioxygenase (immunology, metabolism)
• Inflammation (immunology, metabolism)
• Lipopolysaccharides (immunology, pharmacology)
• Microglia (drug effects, immunology, metabolism)
• Neurons (drug effects, immunology, metabolism)
• Raphe Nuclei (drug effects, immunology, metabolism)
• Rats
• Rats, Sprague-Dawley
• Serotonin (immunology, metabolism)