Neuromodulation by a cytokine: interferon-beta differentially augments neocortical neuronal activity and excitability.
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.
Hadjilambreva
Gergana
G
Department of Neurology, Neurobiological Laboratory, University of Rostock, Gehlsheimer Strasse 20, 18147 Rostock, Germany.
Mix
Eilhard
E
Rolfs
Arndt
A
Müller
Jana
J
Strauss
Ulf
U
D000200:Action Potentials / Q000187:drug effects* / Q000502:physiology; D000818:Animals; D016207:Cytokines / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D016899:Interferon-beta / Q000494:pharmacology*; D008297:Male; D019579:Neocortex / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D018377:Neurotransmitter Agents / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar
D016207:Cytokines; D018377:Neurotransmitter Agents; D016899:Interferon-beta