High-content synaptic phenotyping in human cellular models reveals a role for BET proteins in synapse assembly

Author:

Berryer Martin H12,Rizki Gizem12,Nathanson Anna12,Klein Jenny A12,Trendafilova Darina12,Susco Sara G12,Lam Daisy1,Messana Angelica1,Holton Kristina M12,Karhohs Kyle W3,Cimini Beth A3ORCID,Pfaff Kathleen2,Carpenter Anne E3ORCID,Rubin Lee L12ORCID,Barrett Lindy E12ORCID

Affiliation:

1. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard

2. Department of Stem Cell and Regenerative Biology, Harvard University

3. Imaging Platform, Broad Institute of MIT and Harvard

Abstract

Resolving fundamental molecular and functional processes underlying human synaptic development is crucial for understanding normal brain function as well as dysfunction in disease. Based upon increasing evidence of species-divergent features of brain cell types, coupled with emerging studies of complex human disease genetics, we developed the first automated and quantitative high-content synaptic phenotyping platform using human neurons and astrocytes. To establish the robustness of our platform, we screened the effects of 376 small molecules on presynaptic density, neurite outgrowth, and cell viability, validating six small molecules that specifically enhanced human presynaptic density in vitro. Astrocytes were essential for mediating the effects of all six small molecules, underscoring the relevance of non-cell-autonomous factors in synapse assembly and their importance in synaptic screening applications. Bromodomain and extraterminal (BET) inhibitors emerged as the most prominent hit class and global transcriptional analyses using multiple BET inhibitors confirmed upregulation of synaptic gene expression. Through these analyses, we demonstrate the robustness of our automated screening platform for identifying potent synaptic modulators, which can be further leveraged for scaled analyses of human synaptic mechanisms and drug discovery efforts.

Funder

Stanley Center for Psychiatric Research at the Broad Institute

National Institutes of Health

Publisher

eLife Sciences Publications, Ltd

Subject

General Immunology and Microbiology,General Biochemistry, Genetics and Molecular Biology,General Medicine,General Neuroscience

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