Remodeling of Hyperpolarization-Activated Current, Ih, in Ah-Type Visceral Ganglion Neurons Following Ovariectomy in Adult Rats

Abstract

Hyperpolarization-activated currents (Ih) mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels modulate excitability of myelinated A− and Ah-type visceral ganglion neurons (VGN). Whether alterations in Ih 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 Ih 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 Ih 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 Ih during the preceding spike trains. Ovariectomy reduced whole-cell Ih density, caused a hyperpolarizing shift of the voltage-dependence of Ih activation, and slowed Ih activation. OVX-induced Ih 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 Ih density and accelerated Ih activation in Ah-type cells. In conclusion, Ih plays a significant role in modulating the excitability of myelinated Ah-type VGNs in adult female rats.

Unique Expression of Angiotensin Type-2 Receptor in Sex-Specific Distribution of Myelinated Ah-Type Baroreceptor Neuron Contributing to Sex-Dimorphic Neurocontrol of Circulation

“…12 In Figure 2. addition, our previous data indicated that sex-specific distribution of myelinated Ah-type BRNs are likely to be involved in sex difference of neurocontrol of circulation, 3,13,21,24 which supports the observation that the mRNA expression of AT 2 R was found mainly in myelinated Ah-types by the single-cell RT-PCR analysis ( Figure 2D). Therefore, we hypothesized that Ang-II may excite Ah-type BRNs through AT 2 R-mediated pathway.…”

“…Although a sex difference in AT 2 R expression is identified at first order BRNs, we still do not know the neuron-specific distribution of this receptor simply because vagal ganglion is composed of multiple cell types, including the low-threshold and sex-specific distribution of myelinated Ah-type BRNs, 13,15,17,21 and traditionally classified myelinated A-and unmyelinated C-types. 14,29,40 Thus, it would be extremely important for us to evaluate the AT 2 R expression in identified single cells to understand the cell-specific function in sexual dimorphism of baroreflex.…”

“…In summary, the unique, sex-and afferent-specific expression of AT 2 R was identified in Ah-type BRNs, and AT 2 R-mediated KCa1.1 inhibition in Ah-type BRNs may exert great impacts on baroreflex afferent function and blood pressure regulation in females. 19,20 Ah-type BRNs were rarely found in adult male rats and exhibited an excitability profile that was strongly influenced by circulating sex hormones 3,18,21 and neurotransmitters.…”

“…a female-specific subpopulation of low-threshold myelinated Ah-type baroreceptor neurons (BRNs), which presented not only in NG [13][14][15][16][17][18] but also in NTS. 19,20 Ah-type BRNs were rarely found in adult male rats and exhibited an excitability profile that was strongly influenced by circulating sex hormones 3,18,21 and neurotransmitters. 22,23 Therefore, we speculated that the sex difference and afferent-specificity of AT 2 R expression in myelinated Ah-type BRNs may be greatly involved in the baroreflex afferent function of female rats.…”

Potentiation of 17β-estradiol on neuroexcitability by HCN-mediated neuromodulation of fast-afterhyperpolarization and late-afterdepolarization in low-threshold and sex-specific myelinated Ah-type baroreceptor neurons via GPR30 in female rats

“…Even though the functional downregulation of KCa1.1 in OVX females is responsible at least in part for the decreased neuroexcitability in Ah-type afferents neurons (data not shown), AP waveform seems not significantly altered before and after 17β-E 2 , therefore, the involvement of KCa1.1 in 17β-E 2 -mediated potentiation is largely excluded. Recent investigation has demonstrated that the downregulation of HCN1 expression is one of the plausible molecular mechanisms of less membrane excitation in myelinated Ah-type afferents by surgically removing ovaries [4]. We have also shown that discharge profile can be manipulated by fast…”