Neuromodulation by a Cytokine: Interferon-Beta Differentially Augments Neocortical Neuronal Activity and Excitability

J Neurophysiol. 2005 Feb;93(2):843-52. doi: 10.1152/jn.01224.2003. Epub 2004 Sep 22.

Abstract

The immunomodulatory cytokine interferon-beta (IFN-beta) is used in the treatment of autoimmune diseases such as multiple sclerosis. However, the effect of IFN-beta on neuronal functions is currently unknown. Intracellular recordings were conducted on somatosensory neurons of neocortical layers 2/3 and 5 exposed to IFN-beta. The excitability of neurons was increased by IFN-beta (10-10,000 U/ml) in two kinetically distinct, putatively independent manners. First IFN-beta reversibly influenced the subthreshold membrane response by raising the membrane resistance R(M) 2.5-fold and the membrane time constant tau 1.7-fold dose-dependently. The effect required permanent exposure to IFN-beta and was reduced in magnitude if the extracellular K+ was lowered. However, the membrane response to IFN-beta in the subthreshold range was prevented by ZD7288 (a specific blocker of I(h)) but not by Ni2+, carbachol, or bicuculline, pointing to a dependence on an intact I(h). Second, IFN-beta enhanced the rate of action potential firing. This effect was observed to develop for >1 h when the cell was exposed to IFN-beta for 5 min or >5 min and showed no reversibility (< or =210 min). Current-discharge (F-I) curves revealed a shift (prevented by bicuculline) as well as an increase in slope (prevented by carbachol and Ni2+). Layer specificity was not observed with any of the described effects. In conclusion, IFN-beta influences the neuronal excitability in neocortical pyramidal neurons in vitro, especially under conditions of slightly increased extracellular K+. Our blocker experiments indicate that changes in various ionic conductances with different voltage dependencies cause different IFN-beta influences on sub- and suprathreshold behavior, suggesting a more general intracellular process induced by IFN-beta.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects*
  • Action Potentials / physiology
  • Animals
  • Cytokines / pharmacology*
  • Dose-Response Relationship, Drug
  • In Vitro Techniques
  • Interferon-beta / pharmacology*
  • Male
  • Neocortex / drug effects*
  • Neocortex / physiology
  • Neurons / drug effects
  • Neurons / physiology
  • Neurotransmitter Agents / pharmacology*
  • Rats
  • Rats, Wistar

Substances

  • Cytokines
  • Neurotransmitter Agents
  • Interferon-beta