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Chronic interleukin-6 alters NMDA receptor-mediated membrane responses and enhances neurotoxicity in developing CNS neurons

Academic Article
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Overview

authors

  • Qiu, Z. H.
  • Sweeney, D. D.
  • Netzeband, J. G.
  • Gruol, Donna

publication date

  • December 1998

journal

  • Journal of Neuroscience  Journal

abstract

  • Recent studies show that the cytokine interleukin-6 (IL-6) is expressed at elevated levels in the CNS in several disease states and contributes to the neuropathological process. The mechanisms through which IL-6 exerts its CNS effects are primarily unknown. We have investigated the pathophysiological effects of IL-6 on developing CNS neurons using a culture model system and a chronic treatment paradigm. Here, we show, using current- and voltage-clamp recordings, that chronic IL-6 treatment of developing cerebellar granule neurons increases the membrane and current response to NMDA and that these effects are the primary mechanism through which IL-6 produces an enhanced calcium signal to NMDA. We also show that calcium influx through voltage-sensitive calcium channels contributes to the enhanced calcium signal to NMDA in the IL-6-treated neurons in a developmentally regulated manner and that the membrane depolarization to NMDA is more sensitive to the NMDA receptor antagonist ifenprodil in the IL-6-treated neurons compared with control neurons at a late developmental stage, consistent with a larger proportion of NMDA receptors containing the NMDAR2B subunit in the IL-6-treated neurons. Additional studies show that IL-6 treatment reduces the number of granule neurons in culture and enhances neurotoxicity involving NMDA receptors. These results support a pathological role for IL-6 in the CNS and indicate that NMDA receptor-mediated functions are likely to play a critical role in neuropathological changes observed in CNS diseases associated with elevated CNS levels of IL-6.

subject areas

  • Animals
  • Calcium Channels
  • Calcium Signaling
  • Cell Membrane
  • Cell Survival
  • Cells, Cultured
  • Cerebellum
  • Dose-Response Relationship, Drug
  • Humans
  • In Vitro Techniques
  • Interleukin-6
  • Membrane Potentials
  • N-Methylaspartate
  • Neurons
  • Patch-Clamp Techniques
  • Piperidines
  • Rats
  • Rats, Sprague-Dawley
  • Receptors, N-Methyl-D-Aspartate
  • Time Factors
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Research

keywords

  • CNS neurons
  • NMDA receptors
  • cytokine
  • development
  • interleukin-6
  • intracellular calcium
  • neurotoxicity
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Identity

International Standard Serial Number (ISSN)

  • 0270-6474

PubMed ID

  • 9852582
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Additional Document Info

start page

  • 10445

end page

  • 10456

volume

  • 18

issue

  • 24

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