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 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.
Highlights
HCN channels are expressed in the heart and nervous system and comprise four members (HCN1–HCN4) differing in their kinetics, voltage-dependence and degree of sensitivity to cyclic nucleotides such as cAMP
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, and neuromodulators
The conduction velocity increased by 5.9 ± 2.8% in cerebellar mossy fibers (n = 17), by 3.7 ± 1.4% in parallel fibers (n = 10), and by 4.6 ± 0.6% in optic nerves (n = 5; see Fig. 1 and legend for statistical testing). These results indicate that HCN channels control the conduction velocity both in myelinated and non-myelinated central axons. 116 Neuromodulators differentially regulate conduction velocity To investigate a modulation of conduction velocity by physiological neuromodulators, we focused on the cerebellar parallel fibers, where the velocity could be most accurately measured, and applied several modulators known to act via cAMP-dependent pathways (Fig. 2)
Summary
Patch-clamp recordings from dendrites in pyramidal neurons have revealed high densities of HCN channels which acts to control the local resting potential and leak conductance, thereby playing important roles in regulating synaptic integration (George et al, 2009; Harnett et al, 2015; Kole et al, 2006; Magee, 1999; Williams and Stuart, 2000). Computational modelling indicated that the resting membrane potential controls conduction velocity and that the activity of HCN channel is metabolically expensive. These data reveal a mechanism shared among different types of axons to bidirectionally modulate conduction velocity in the central nervous system
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