Neuromodulation by a Cytokine: Interferon-β differentially augments neocortical neuronal activity and excitability

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