Human iPSC‐Derived Cerebral Organoids Reveal Altered Neuronal Excitability in Subjects with Monge's Disease
Authors: Wu Wei , Yao Hang , Zhao Huiwen , Negraes Priscilla Davidson , Muotri Alysson , Haddad Gabriel 
Published: June 2021

Monge's disease, also called chronic mountain sickness (CMS), is a disease afflicting residents who live at high altitudes (>2500 m) for an extended time. The occurrence of CMS can be as high as 20% while most highlanders (non‐CMS) are rather healthy. Many neurologic manifestations are developed in CMS subjects including migraine, mental fatigue, confusion, dizziness, and memory loss, but the molecular mechanisms underlying CMS neuropathology is poorly understood. We developed an iPSC‐derived cerebral organoid from CMS patients, non‐CMS subjects and sea level subjects. The organoids were attached to the dish to grow and the majority of the cells spreading from the organoids express neural markers including MAP2 and TuJ1. Patch clamp technique was employed to study cellular electrophysiological properties. Cells in cerebral organoids having voltage‐gated sodium currents and evoked action potential were considered as functional neurons. The resting membrane potential (RMP) of iPSC‐derived neurons from CMS subjects (−57.1±2.8 mV, n=17) were not significantly different as compared to those from non‐CMS subjects (−58.9±1.3 mV, n=33, p>0.05) and sea level control subjects (−58.6±1.7 mV, n=21, p>0.05). The amplitude of evoked action potential in CMS neurons (44.9±3.0 mV, n=11) was higher than the amplitudes in non‐CMS subject (38.8±1.5 mV, n=34, p<0.05) and sea level subject (37.7±3.2 mV, n=10, p<0.01). We further discovered that the current densities of voltage‐gated sodium channels of iPSC‐derived neurons from CMS subjects (−139.4±14.3 pA/pF at −20 mV, n=13) were significantly higher than those from non‐CMS subjects (−88.1±7.9 pA/pF at −20 mV, n=27, p<0.01) and sea level subjects (−85.7±13.2 pA/pF at −20 mV, n=15, p<0.01) which can explain the increased action potential amplitude in CMS neurons. The steady‐state gating properties (both activation and inactivation) of sodium channels from CMS neurons were similar to those from non‐CMS and sea level ones. In addition, there were no significant differences of outward potassium currents of iPSC‐derived neurons between CMS and non‐CMS subject. Overall, We found that electrophysiological properties (e.g., RMP, action potential, sodium channel expression) of iPSC‐derived neurons in cerebral organoids were much more mature than those of previously iPSC‐derived neurons using monolayer differentiation protocol [HW Zhao, et al., Neuroscience 2015]. Based on this cerebral organoid model, our findings provide new evidence of increased neuronal excitability based on increased sodium channel current densities in iPSC‐derived neurons from CMS patients. The findings may explain the neurologic symptoms in CMS patients such as migraine, confusion and memory loss.Support or Funding InformationThis project was supported by NIH 1R21NS097899.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.