HCN channel-mediated neuromodulation can control action potential velocity and fidelity in central axons

Hyperpolarization-activated cyclic-nucleotide-gated (HCN) channels control electrical rhythmicity and excitability in the heart and brain, but the function of HCN channels at subcellular level in axons remains poorly understood. Here, we show that the action potential conduction velocity in both myelinated and unmyelinated central axons can bidirectionally be modulated by HCN channel blockers, cyclic adenosine monophosphate (cAMP), and neuromodulators. Recordings from mice 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 accord, immunogold-electron microscopy revealed HCN2 as the dominating subunit in cerebellar mossy fibers. Computational modeling indicated that HCN2 channels control conduction velocity primarily via altering the resting membrane potential and was associated with significant metabolic costs. These results suggest that the cAMP-HCN pathway provides neuromodulators an opportunity to finely tune energy consumption and temporal delays across axons in the brain.