Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations

TY - JOUR

T1 - Elevation in type I interferons inhibits HCN1 and slows cortical neuronal oscillations

AU - Stadler, Konstantin

AU - Bierwirth, Claudia

AU - Stoenica, Luminita

AU - Battefeld, Arne

AU - Reetz, Olivia

AU - Mix, Eilhard

AU - Schuchmann, Sebastian

AU - Velmans, Tanja

AU - Rosenberger, Karen

AU - Bräuer, Anja U

AU - Lehnardt, Seija

AU - Nitsch, Robert

AU - Budt, Matthias

AU - Wolff, Thorsten

AU - Kole, Maarten H P

AU - Strauss, Ulf

PY - 2014/1

Y1 - 2014/1

N2 - Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization-activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected. The effect required an intact type I receptor (IFNAR) signaling cascade. Consistent with Ih inhibition, IFNs hyperpolarized the resting membrane potential, shifted the resonance frequency, and increased the membrane impedance. In vivo application of IFN-β to the rat and to the mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity only in the presence of HCN1. In summary, these findings identify HCN1 channels as a novel neural target for type I IFNs providing the possibility to tune neural responses during the complex event of a CNS inflammation.

AB - Central nervous system (CNS) inflammation involves the generation of inducible cytokines such as interferons (IFNs) and alterations in brain activity, yet the interplay of both is not well understood. Here, we show that in vivo elevation of IFNs by viral brain infection reduced hyperpolarization-activated currents (Ih) in cortical pyramidal neurons. In rodent brain slices directly exposed to type I IFNs, the hyperpolarization-activated cyclic nucleotide (HCN)-gated channel subunit HCN1 was specifically affected. The effect required an intact type I receptor (IFNAR) signaling cascade. Consistent with Ih inhibition, IFNs hyperpolarized the resting membrane potential, shifted the resonance frequency, and increased the membrane impedance. In vivo application of IFN-β to the rat and to the mouse cerebral cortex reduced the power of higher frequencies in the cortical electroencephalographic activity only in the presence of HCN1. In summary, these findings identify HCN1 channels as a novel neural target for type I IFNs providing the possibility to tune neural responses during the complex event of a CNS inflammation.

KW - Animals

KW - Blotting, Western

KW - Cerebral Cortex

KW - Computer Simulation

KW - Cytokines

KW - Electroencephalography

KW - Electrophysiological Processes

KW - HEK293 Cells

KW - Humans

KW - Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels

KW - Immunohistochemistry

KW - Interferon Type I

KW - Interferon-beta

KW - Male

KW - Mice, Inbred C57BL

KW - Neocortex

KW - Nerve Net

KW - Neurons

KW - Patch-Clamp Techniques

KW - Potassium Channels

KW - Rats

KW - Real-Time Polymerase Chain Reaction

KW - Receptors, Interferon

KW - Signal Transduction

KW - Transfection

U2 - 10.1093/cercor/bhs305

DO - 10.1093/cercor/bhs305

M3 - Article

C2 - 23042740

SN - 1047-3211

VL - 24

SP - 199

EP - 210

JO - Cerebral Cortex

JF - Cerebral Cortex

IS - 1

ER -