Muscarinic acetylcholine receptors modulate HCN channel properties in vestibular ganglion neurons
Vestibular efferent neurons play an important role in shaping vestibular afferent excitability and accordingly, on the information encoded by their spike patterns. Efferent-modulation is linked to muscarinic signaling cascades that affect ion channel conductances, most notably low-voltage gated potassium channels such as KCNQ. Here we tested and found that muscarinic signaling cascades also modulate hyperpolarization-activated cyclic-nucleotide gated channels (HCN). HCN channels play a key role in controlling spike-timing regularity and a non-chemical form of transmission between type I hair cells and vestibular afferents. The impact of cholinergic efferent input on HCN channels was assessed using voltage-clamp methods, which measure currents in the disassociated cell bodies of vestibular ganglion neurons (VGN). Membrane properties in VGN were characterized before and after administration of the muscarinic acetylcholine receptor (mAChR) agonist Oxotremorine-M (Oxo-M). We found that Oxo-M shifted the voltage-activation range of HCN channels in the positive direction by 4.1 +/- 1.1 mV, which more than doubled the available current when held near rest at -60 mV (a 184 +/- 90.1% increase, n=19). This effect was not blocked by pre-treating the cells with a KCNQ channel blocker, linopirdine, which suggests that this effect is not dependent on KCNQ currents. We also found that HCN channel properties in the baseline condition and sensitivity to mAChR activation depended on cell size and firing patterns. Large-bodied neurons with onset firing patterns had the most depolarized activation range and least sensitivity to mAChR activation. Together, our results highlight the complex and dynamic regulation of HCN channels in VGN.