Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls

• Main Authors: Swagata Ghatak, Nima Dolatabadi, Dorit Trudler, XiaoTong Zhang, Yin Wu, Madhav Mohata, Rajesh Ambasudhan, Maria Talantova, Stuart A Lipton
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2019-11-01
• Series: eLife
• Subjects: Alzheimer's disease; hyperexcitability; hiPSC derived neuronal cultures; cerebral organoids
• Online Access: https://elifesciences.org/articles/50333

Human Alzheimer’s disease (AD) brains and transgenic AD mouse models manifest hyperexcitability. This aberrant electrical activity is caused by synaptic dysfunction that represents the major pathophysiological correlate of cognitive decline. However, the underlying mechanism for this excessive excitability remains incompletely understood. To investigate the basis for the hyperactivity, we performed electrophysiological and immunofluorescence studies on hiPSC-derived cerebrocortical neuronal cultures and cerebral organoids bearing AD-related mutations in presenilin-1 or amyloid precursor protein vs. isogenic gene corrected controls. In the AD hiPSC-derived neurons/organoids, we found increased excitatory bursting activity, which could be explained in part by a decrease in neurite length. AD hiPSC-derived neurons also displayed increased sodium current density and increased excitatory and decreased inhibitory synaptic activity. Our findings establish hiPSC-derived AD neuronal cultures and organoids as a relevant model of early AD pathophysiology and provide mechanistic insight into the observed hyperexcitability.