Proinflammatory cytokines differentially influence adult hippocampal cell proliferation depending upon the route and chronicity of administration

Abstract

Disturbances of hippocampal plasticity, including impaired dendritic branching and reductions of neurogenesis, are provoked by stressful insults and may occur in depression. Although corticoids likely contribute to stressor-induced reductions of neurogenesis, other signaling messengers, including pro-inflammatory cytokines might also be involved. Accordingly, the present investigation assessed whether three proinflammatory cytokines, namely interleukin-1β (IL-1β), IL-6, and tumor necrosis factor-α (TNF-α) (associated with depression) influenced cellular proliferation within the hippocampus. In this regard, systemic administration of TNF-α reduced 5-bromo-2-deoxyuridine (BrdU) labeling within the hippocampus, whereas IL-1β and IL-6 had no such effect. However, repeated but not a single intra-hippocampal infusion of IL-6 and IL-1β actually increased cellular proliferation and IL-6 infusion also enhanced microglial staining within the hippocampus. Yet, no changes in doublecortin expression were apparent, suggesting that the cytokine did not influence the birth of cells destined to become neurons. Essentially, the route of administration and chronicity of cytokine administration had a marked influence upon the nature of hippocampal alterations provoked, suggesting that cytokines may differentially regulate hippocampal plasticity in neuropsychiatric conditions.

Keywords:

• cytokine
• depression
• neuroplasticity
• hippocampus
• stressor

Acknowledgements

The technical assistance of M Zhang and G Mott is greatly appreciated. We also thank H Anisman for critical evaluation of the manuscript. S Hayley is a Canada Research Chair (Tier 2) in Neuroscience. This work was supported by funds awarded to S Hayley from the Natural Sciences and Engineering Research Council (NSERC) and Canadian Institutes of Health Research (CIHR) Canada, as well as a New Investigator Awards from NARSAD.