Down-regulation of Inwardly Rectifying K⁺ Currents in Astrocytes Derived from Patients with Monge's Disease

Chronic mountain sickness (CMS) or Monge's disease is a disease in highlanders. These patients have a variety of neurologic symptoms such as migraine, mental fatigue, confusion, dizziness, loss of appetite, memory loss and neuronal degeneration. The cellular and molecular mechanisms underlying CMS neuropathology is not understood. In the previous study, we demonstrated that neurons derived from CMS patients' fibroblasts have a decreased expression and altered gating properties of voltage-gated sodium channel. In this study, we further characterize the electrophysiological properties of iPSC-derived astrocytes from CMS patients. We found that the current densities of the inwardly rectifying potassium (Kir) channels in CMS astrocytes (-5.7 ± 2.2 pA/pF at -140 mV) were significantly decreased as compared to non-CMS (-28.4 ± 3.4 pA/pF at -140 mV) and sea level subjects (-28.3 ± 5.3 pA/pF at -140 mV). We further demonstrated that the reduced Kir current densities in CMS astrocytes were caused by their decreased protein expression of Kir4.1 and Kir2.3 channels, while single channel properties (i.e., P_o, conductance) of Kir channel in CMS astrocytes were not altered. In addition, we found no significant differences of outward potassium currents between CMS and non-CMS astrocytes. As compared to non-CMS and sea level subjects, the K⁺ uptake ability in CMS astrocytes was significantly decreased. Taken together, our results suggest that down-regulation of Kir channels and the resulting decreased K⁺ uptake ability in astrocytes could be one of the major molecular mechanisms underlying the neurologic manifestations in CMS patients.