Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls
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 excit...
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| Format: | Article |
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eLife Sciences Publications Ltd
2019-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/50333 |
| _version_ | 1811235962048479232 |
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| author | Swagata Ghatak Nima Dolatabadi Dorit Trudler XiaoTong Zhang Yin Wu Madhav Mohata Rajesh Ambasudhan Maria Talantova Stuart A Lipton |
| author_facet | Swagata Ghatak Nima Dolatabadi Dorit Trudler XiaoTong Zhang Yin Wu Madhav Mohata Rajesh Ambasudhan Maria Talantova Stuart A Lipton |
| author_sort | Swagata Ghatak |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-12T12:01:05Z |
| format | Article |
| id | doaj.art-31d6c80f1cdd4aa0ba5795f6be3ccee7 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T12:01:05Z |
| publishDate | 2019-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-31d6c80f1cdd4aa0ba5795f6be3ccee72022-12-22T03:33:50ZengeLife Sciences Publications LtdeLife2050-084X2019-11-01810.7554/eLife.50333Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controlsSwagata Ghatak0Nima Dolatabadi1Dorit Trudler2https://orcid.org/0000-0002-5835-3322XiaoTong Zhang3Yin Wu4Madhav Mohata5Rajesh Ambasudhan6Maria Talantova7Stuart A Lipton8https://orcid.org/0000-0002-3490-1259Department of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesNeurodegenerative Disease Center, Scintillon Institute, San Diego, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United StatesDepartment of Molecular Medicine, The Scripps Research Institute, La Jolla, United States; Neurodegenerative Disease Center, Scintillon Institute, San Diego, United States; Department of Neuroscience, The Scripps Research Institute, La Jolla, United States; Neuroscience Translational Center, The Scripps Research Institute, La Jolla, United States; Department of Neurosciences, School of Medicine, University of California, San Diego, San Diego, United StatesHuman 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.https://elifesciences.org/articles/50333Alzheimer's diseasehyperexcitabilityhiPSC derived neuronal culturescerebral organoids |
| spellingShingle | Swagata Ghatak Nima Dolatabadi Dorit Trudler XiaoTong Zhang Yin Wu Madhav Mohata Rajesh Ambasudhan Maria Talantova Stuart A Lipton Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls eLife Alzheimer's disease hyperexcitability hiPSC derived neuronal cultures cerebral organoids |
| title | Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls |
| title_full | Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls |
| title_fullStr | Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls |
| title_full_unstemmed | Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls |
| title_short | Mechanisms of hyperexcitability in Alzheimer’s disease hiPSC-derived neurons and cerebral organoids vs isogenic controls |
| title_sort | mechanisms of hyperexcitability in alzheimer s disease hipsc derived neurons and cerebral organoids vs isogenic controls |
| topic | Alzheimer's disease hyperexcitability hiPSC derived neuronal cultures cerebral organoids |
| url | https://elifesciences.org/articles/50333 |
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