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

J Neurosci. 1998 Dec 15;18(24):10445-56. doi: 10.1523/JNEUROSCI.18-24-10445.1998.


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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

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


  • Calcium Channels
  • Interleukin-6
  • Piperidines
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • ifenprodil