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Neuromodulation by a cytokine: interferon-beta differentially augments neocortical neuronal activity and excitability
Gergana Hadjilambreva1, Eilhard Mix, Arndt Rolfs
1Department of Neurology, Neurobiological Laboratory, University of Rostock, Gehlsheimer Strasse 20, 18147 Rostock, Germany.
Insights
Interferon-beta (IFN-beta), used for autoimmune diseases, increases neuronal excitability in the neocortex by altering membrane properties and action potential firing. This suggests a broader intracellular mechanism influencing neuronal function.
Area of Science:
- Neuroscience
- Immunology
- Cellular Biology
Background:
- Interferon-beta (IFN-beta) is an immunomodulatory cytokine used to treat autoimmune conditions like multiple sclerosis.
- The impact of IFN-beta on neuronal function, particularly in the central nervous system, remains largely uncharacterized.
- Understanding IFN-beta's effects on neurons is crucial for evaluating its broader physiological and potential neurological consequences.
Purpose of the Study:
- To investigate the effects of interferon-beta (IFN-beta) on the excitability of neocortical pyramidal neurons in vitro.
- To elucidate the specific ionic mechanisms underlying IFN-beta's influence on neuronal subthreshold and suprathreshold activity.
- To determine if IFN-beta exerts layer-specific effects on neuronal excitability.
Main Methods:
- Intracellular recordings were performed on somatosensory neurons from layers 2/3 and 5 of the neocortex.
- Neurons were exposed to varying concentrations of IFN-beta (10-10,000 U/ml).
- Pharmacological blockers (ZD7288, Ni2+, carbachol, bicuculline) and altered extracellular potassium concentrations were used to probe ionic conductances and signaling pathways.
Main Results:
- IFN-beta dose-dependently increased neuronal excitability through two distinct mechanisms.
- Subthreshold effects included a reversible increase in membrane resistance and time constant, dependent on intact I(h) and extracellular K+.
- Suprathreshold effects involved enhanced action potential firing rate, characterized by a shift and increased slope in current-discharge curves, with different ionic dependencies and irreversibility.
Conclusions:
- IFN-beta significantly modulates neocortical pyramidal neuron excitability in vitro.
- The observed effects involve alterations in multiple voltage-dependent ionic conductances, suggesting a complex intracellular signaling cascade induced by IFN-beta.
- IFN-beta's influence on neuronal excitability may be particularly pronounced under conditions mimicking mild neuronal stress, such as slightly elevated extracellular K+.
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.
