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

被引：152

作者：

Ghatak, Swagata ^{[1
]}

Dolatabadi, Nima ^{[1
]}

Trudler, Dorit ^{[1
]}

Zhang, XiaoTong ^{[1
]}

Wu, Yin ^{[1
]}

Mohata, Madhav ^{[1
]}

Ambasudhan, Rajesh ^{[2
]}

Talantova, Maria ^{[1
]}

Lipton, Stuart A. ^{[1
,2
,3
,4
,5
]}

机构：

[1] Scripps Res Inst, Dept Mol Med, La Jolla, CA 92037 USA

[2] Scintillon Inst, Neurodegenerat Dis Ctr, San Diego, CA 92121 USA

[3] Scripps Res Inst, Dept Neurosci, La Jolla, CA 92037 USA

[4] Scripps Res Inst, Neurosci Translat Ctr, La Jolla, CA 92037 USA

[5] Univ Calif San Diego, Sch Med, Dept Neurosci, San Diego, CA 92103 USA

来源：

ELIFE | 2019年 / 8卷

基金：

美国国家卫生研究院;

关键词：

GATED SODIUM-CHANNELS; RELEASE PROBABILITY; AMYLOID-BETA; SYNAPSE LOSS; DYSFUNCTION; SUBUNITS; IMPAIRMENTS; SEIZURES; VGLUT1; CORTEX;

D O I：

10.7554/eLife.50333

中图分类号：

Q [生物科学];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：22

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