Functional impact of the hyperpolarization-activated current upon the excitability of myelinated A-type vagal afferents neurons in rat

The hyperpolarization induced cation selective current, I h , is widely observed in peripheral sensory neurons of the vagal and dorsal root ganglia but the peak magnitude as well as the voltage and time dependent properties of this current vary widely across afferent fiber type. Through patch clamp study of isolated rat vagal ganglion neurons identified as myelinated A-type afferents we establish a compendium of functional correlates between changes in membrane potential and the dynamic discharge properties of these sensory neurons as a result of the controlled recruitment of I h using the current clamp technique. Two robust observations in response to hyperpolarizing step currents: 1) upon initiation of the negative step current there was a rapid hyperpolarization of membrane potential followed by a depolarizing sag (DVS) toward a plateau in membrane potential as a result of steady state recruitment of I h , and 2) upon termination of the negative step current there was a rapid return to the pretest resting membrane potential that often led to spontaneous action potential discharge. These data strongly correlated (r 2 > 0.9) with a broad compendium of dynamic discharge characteristics in these A-type VGN. In response to depolarizing step currents of increasing magnitude the discharge frequency of the A-type VGN summarize reliably responded with increases in the rate of sustained repetitive discharge. Upon termination of the depolarizing step current there was a post excitatory membrane hyperpolarization with a magnitude that strongly correlated with action potential discharge rate (r 2 > 0.9). Application of the selective HCN channel blockers 10 µM ZD7288 or 1.0 mM CsCl abolished I h and all of the aforementioned functional correlates in addition to reducing the excitability of the A-type VGN to step depolarizing currents. As evidence is growing that the HCN channel current may represent a valid target for pharmacological intervention such quantitative relationships could potentially help guide the molecular or chemical modification of HCN channel gating properties to effect a particular outcome in VGN discharge properties. Ideally, well beyond merely selective blockade of a particular HCN channel subtype.