A Single-Cell Model for Synaptic Transmission and Plasticity in Human iPSC-Derived Neurons

Marieke Meijer, Kristina Rehbach, Jessie W. Brunner, Jessica A. Classen, Hanna C.A. Lammertse, Lola A. van Linge, Desiree Schut, Tamara Krutenko, Matthias Hebisch, L. Niels Cornelisse, Patrick F. Sullivan, Michael Peitz*, Ruud F. Toonen, Oliver Brüstle, Matthijs Verhage

*Corresponding author for this work

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

Synaptic dysfunction is associated with many brain disorders, but robust human cell models to study synaptic transmission and plasticity are lacking. Instead, current in vitro studies on human neurons typically rely on spontaneous synaptic events as a proxy for synapse function. Here, we describe a standardized in vitro approach using human neurons cultured individually on glia microdot arrays that allow single-cell analysis of synapse formation and function. We show that single glutamatergic or GABAergic forebrain neurons differentiated from human induced pluripotent stem cells form mature synapses that exhibit robust evoked synaptic transmission. These neurons show plasticity features such as synaptic facilitation, depression, and recovery. Finally, we show that spontaneous events are a poor predictor of synaptic maturity and do not correlate with the robustness of evoked responses. This methodology can be deployed directly to evaluate disease models for synaptic dysfunction and can be leveraged for drug development and precision medicine. This multisite study by Meijer et al. establishes a standardized in vitro approach to study synapse formation and function in single iPSC-derived human neurons. They validate this approach for GABA and glutamatergic human neurons. The methodology is scalable and suitable for compound screening and disease modeling.

Original languageEnglish
Pages (from-to)2199-2211.e6
JournalCell Reports
Volume27
Issue number7
DOIs
Publication statusPublished - 14 May 2019

Funding

We thank Vincent Huson and Jurjen Broeke for developing scripts to analyze the physiological data and Frank den Oudsten for producing glia microdot arrays. We acknowledge Sven Stringer and Josefin Werme for expert help with identifying copy number variants from SNP arrays. We thank Dr. Su-Chun Zhang for kindly providing the AAVS targeting vector and corresponding TALEN plasmids. We gratefully acknowledge the technical support of Tamara Bechler. The research leading to these results has received funding from COSYN ( Comorbidity and Synapse Biology in Clinically Overlapping Psychiatric Disorders ; to M.V., P.F.S., and O.B.) (Horizon 2020 Program of the European Union under RIA grant agreement 667301 ); a European Research Council (ERC) advanced grant ( 322966 ) of the European Union (to M.V.), and the German Federal Ministry of Education and Research (BMBF) within the framework of the e:Med research and funding concept (grant 01ZX1314A-IntegraMent to O.B.).

FundersFunder number
COSYN
Horizon 2020 Framework Programme667301, 322966
European Commission
European Research Council
Royal Irish Academy
Bundesministerium für Bildung und Forschung01ZX1314A-IntegraMent
Horizon 2020

    Keywords

    • forward programming
    • human neuron
    • iPSC
    • NGN2
    • single-cell model
    • synapse
    • synaptic dysfunction
    • synaptic plasticity
    • synaptic transmission
    • synaptopathy

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