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Free keywords:
HCN; axon; conduction velocity; mouse; neuromodulation; neuroscience.
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 (EC50 40 mM; estimated
endogenous cAMP concentration 13 mM). 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.
