Remodeling of Hyperpolarization-Activated Current, I(h), in Ah-Type Visceral Ganglion Neurons Following Ovariectomy in Adult Rats

Hyperpolarization-activated currents (I(h)) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate excitability of myelinated A− and Ah-type visceral ganglion neurons (VGN). Whether alterations in I(h) underlie the previously reported reduction of excitability of myelinated Ah-type VGNs following ovariectomy (OVX) has remained unclear. Here we used the intact nodose ganglion preparation in conjunction with electrophysiological approaches to examine the role of I(h) remodeling in altering Ah-type neuron excitability following ovariectomy in adult rats. Ah-type neurons were identified based on their afferent conduction velocity. Ah-type neurons in nodose ganglia from non-OVX rats exhibited a voltage ‘sag’ as well as ‘rebound’ action potentials immediately following hyperpolarizing current injections, which both were suppressed by the I(h) blocker ZD7288. Repetitive spike activity induced afterhyperpolarizations lasting several hundreds of milliseconds (termed post-excitatory membrane hyperpolarizations, PEMHs), which were significantly reduced by ZD7288, suggesting that they resulted from transient deactivation of I(h) during the preceding spike trains. Ovariectomy reduced whole-cell I(h) density, caused a hyperpolarizing shift of the voltage-dependence of I(h) activation, and slowed I(h) activation. OVX-induced I(h) remodeling was accompanied by a flattening of the stimulus frequency/response curve and loss of PEMHs. Also, HCN1 mRNA levels were reduced by ∼30% in nodose ganglia from OVX rats compared with their non-OVX counterparts. Acute exposure of nodose ganglia to 17beta-estradiol partly restored I(h) density and accelerated I(h) activation in Ah-type cells. In conclusion, I(h) plays a significant role in modulating the excitability of myelinated Ah-type VGNs in adult female rats.