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

Abstract:

: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.

journal_name

Cell Stem Cell

journal_title

Cell stem cell

authors

Sarkar A,Mei A,Paquola ACM,Stern S,Bardy C,Klug JR,Kim S,Neshat N,Kim HJ,Ku M,Shokhirev MN,Adamowicz DH,Marchetto MC,Jappelli R,Erwin JA,Padmanabhan K,Shtrahman M,Jin X,Gage FH

doi

10.1016/j.stem.2018.04.009

subject

Has Abstract

pub_date

2018-05-03 00:00:00

pages

684-697.e9

issue

5

eissn

1934-5909

issn

1875-9777

pii

S1934-5909(18)30171-1

journal_volume

22

pub_type

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