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Publication

Efficient Generation of CA3 Neurons from Human Pluripotent Stem Cells Enables Modeling of Hippocampal Connectivity In Vitro.

Cell stem cell | 2018

Despite widespread interest in using human induced pluripotent stem cells (hiPSCs) in neurological disease modeling, a suitable model system to study human neuronal connectivity is lacking. Here, we report a comprehensive and efficient differentiation paradigm for hiPSCs that generate multiple CA3 pyramidal neuron subtypes as detected by single-cell RNA sequencing (RNA-seq). This differentiation paradigm exhibits characteristics of neuronal network maturation, and rabies virus tracing revealed synaptic connections between stem cell-derived dentate gyrus (DG) and CA3 neurons in vitro recapitulating the neuronal connectivity within the hippocampus. Because hippocampal dysfunction has been implicated in schizophrenia, we applied DG and CA3 differentiation paradigms to schizophrenia-patient-derived hiPSCs. We detected reduced activity in DG-CA3 co-culture and deficits in spontaneous and evoked activity in CA3 neurons from schizophrenia-patient-derived hiPSCs. Our approach offers critical insights into the network activity aspects of schizophrenia and may serve as a promising tool for modeling diseases with hippocampal vulnerability. VIDEO ABSTRACT.

Pubmed ID: 29727680 RIS Download

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Associated grants

Agency: NIMH NIH HHS, United States
Id: R01 MH113924
Agency: NIMH NIH HHS, United States
Id: K99 MH101634
Agency: NIMH NIH HHS, United States
Id: R00 MH101634
Agency: NIMH NIH HHS, United States
Id: U19 MH106434
Agency: NIMH NIH HHS, United States
Id: U01 MH106882
Agency: NINDS NIH HHS, United States
Id: K08 NS093130
Agency: NINDS NIH HHS, United States
Id: P30 NS072031

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Shiley-Marcos Alzheimer's Disease Research Center (tool)

RRID:SCR_001928

The UCSD ADRC conducts a wide variety of research studies dedicated to understanding the causes, clinical features, and treatments for Alzheimer's disease and related memory disorders. The goal of the center is to discover ways to prevent and eradicate the disease. The Center aims to maintain research subjects, clinical resources, and clinical data to support ongoing and proposed research and to assist in the development of new clinical and interdisciplinary research. An Alzheimer's brain bank with well characterized cases, including Mild Cognitive Impairment and Lewy Body disease, is maintained at the Center.

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HTSeq (tool)

RRID:SCR_005514

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RRID:SCR_015899

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RRID:SCR_016308

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Illumina HiSeq 2500 System (tool)

RRID:SCR_016383

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