HCN Channel-mediated Neuromodulation Can Control Action Potential Velocity and Fidelity in Central Axons

Overview

Journal Elife

Specialty Biology

Date 2019 Sep 10

PMID 31496517

Citations 20

Authors

Niklas Byczkowicz

Abdelmoneim Eshra

Jacqueline Montanaro

Andrea Trevisiol

Johannes Hirrlinger

Maarten Hp Kole

Ryuichi Shigemoto

Stefan Hallermann

Affiliations

Soon will be listed here.

Abstract

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at the subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can be bidirectionally modulated by a HCN channel blocker, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mouse cerebellar mossy fiber boutons show that HCN channels ensure reliable high-frequency firing and are strongly modulated by cAMP (EC 40 µM; estimated endogenous cAMP concentration 13 µM). In addition, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily by altering the resting membrane potential and are associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators with an opportunity to finely tune energy consumption and temporal delays across axons in the brain.

Citing Articles

The influence of hyperpolarization-activated cation current on conduction delay and failure of action potentials along axon related to abnormal functions.

Lu M, Gu H, Zhang X Cogn Neurodyn. 2024; 18(5):2433-2453.

PMID: 39555253 PMC: 11564431. DOI: 10.1007/s11571-024-10103-2.

HCN1 hyperpolarization-activated cyclic nucleotide-gated channels enhance evoked GABA release from parvalbumin-positive interneurons.

Buss E, Lofaro O, Barnett A, Leroy F, Santoro B, Siegelbaum S Proc Natl Acad Sci U S A. 2024; 121(42):e2319246121.

PMID: 39378096 PMC: 11494348. DOI: 10.1073/pnas.2319246121.

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Screening effects of HCN channel blockers on sleep/wake behavior in zebrafish.

Doldur-Balli F, Smieszek S, Keenan B, Zimmerman A, Veatch O, Polymeropoulos C Front Neurosci. 2024; 18:1375484.

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Protein kinase Cγ negatively regulates the intrinsic excitability in zebrin-negative cerebellar Purkinje cells.

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