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

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 comp...

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Published in:eLife 2023-04, Vol.12
Main Authors: Berryer, Martin H, Rizki, Gizem, Nathanson, Anna, Klein, Jenny A, Trendafilova, Darina, Susco, Sara G, Lam, Daisy, Messana, Angelica, Holton, Kristina M, Karhohs, Kyle W, Cimini, Beth A, Pfaff, Kathleen, Carpenter, Anne E, Rubin, Lee L, Barrett, Lindy E
Format: Article
Language:English
Subjects:
Astrocytes
Drug discovery
Genetic transcription
human
Humans
iPSC
Medical research
Medicine, Experimental
Neurogenesis - physiology
Neuronal Outgrowth
Neurons
Neurons - physiology
Neurophysiology
Neuroscience
Scientific equipment and supplies industry
screening platform
Stem Cells and Regenerative Medicine
synapse
Synapses - physiology
Tools and Resources
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Summary: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.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.80168