Hypoxia with inflammation and reperfusion alters membrane resistance by dynamically regulating voltage-gated potassium channels in hippocampal CA1 neurons

Yoon-Sil Yang,Joon Ho Choi,Jong-Cheol Rah

doi:10.1186/s13041-021-00857-9

Abstract

Hypoxia typically accompanies acute inflammatory responses in patients and animal models. However, a limited number of studies have examined the effect of hypoxia in combination with inflammation (Hypo-Inf) on neural function. We previously reported that neuronal excitability in hippocampal CA1 neurons decreased during hypoxia and greatly rebounded upon reoxygenation. We attributed this altered excitability mainly to the dynamic regulation of hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels and input resistance. However, the molecular mechanisms underlying input resistance changes by Hypo-Inf and reperfusion remained unclear. In the present study, we found that a change in the density of the delayed rectifier potassium current (IDR) can explain the input resistance variability. Furthermore, voltage-dependent inactivation of A-type potassium (IA) channels shifted in the depolarizing direction during Hypo-Inf and reverted to normal upon reperfusion without a significant alteration in the maximum current density. Our results indicate that changes in the input resistance, and consequently excitability, caused by Hypo-Inf and reperfusion are at least partially regulated by the availability and voltage dependence of KV channels. Moreover, these results suggest that selective KV channel modulators can be used as potential neuroprotective drugs to minimize hypoxia- and reperfusion-induced neuronal damage.

Highlights

Hypoxia typically accompanies inflammatory responses in patients with stroke or ischemia and in animal models through hypoxia-inducible factor (HIF) and nuclear factor-kB (NF-kB) [1,2,3,4,5,6]
The input resistance change coincided with the frequency of action potential (AP) in response to Hypo-Inf and reoxygenation, suggesting that the input resistance change could contribute to the excitability of the neuron and that voltage-dependent sodium channels were not responsible for this change (Fig. 1c)
We found that the maximum A-type potassium current (IA) density was unchanged during Hypo-Inf and reperfusion, indicating that input resistance during and after Hypo-Inf did not originate from the availability of IA channels on the surface of the neurons

Summary

Introduction

Hypoxia typically accompanies inflammatory responses in patients with stroke or ischemia and in animal models through hypoxia-inducible factor (HIF) and nuclear factor-kB (NF-kB) [1,2,3,4,5,6]. Various inflammatory responses of the brain cause hypoxia by reducing cerebral blood flow [7]. The molecular mechanisms underlying input resistance changes remain to be determined. Such input resistance changes are likely independent of the hyperpolarization-activated current (Ih) change because Ih changes in an opposite direction relative to the input resistance. As HCN channels will be partially open constitutively at the resting membrane potential (RMP), the recruitment of HCN channels would decrease the input resistance [13, 14], which is opposite to our observation

Methods

Results

Conclusion