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Synapse microarray identification of small molecules that enhance synaptogenesis

Author

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  • Peng Shi

    (Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
    Present address: Department of Mechanical and Biomedical Engineering, City University of Hong Kong, Kowloon, Hong Kong, China.)

  • Mark A. Scott

    (Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.)

  • Balaram Ghosh

    (Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.)

  • Dongpeng Wan

    (Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.)

  • Zachary Wissner-Gross

    (Harvard University)

  • Ralph Mazitschek

    (Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA.)

  • Stephen J. Haggarty

    (Center for Human Genetic Research, Massachusetts General Hospital, Harvard Medical School
    Broad Institute of Harvard and MIT)

  • Mehmet Fatih Yanik

    (Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
    Broad Institute of Harvard and MIT
    Massachusetts Institute of Technology)

Abstract

Synaptic function is affected in many brain diseases and disorders. Technologies for large-scale synapse assays can facilitate identification of drug leads. Here we report a 'synapse microarray' technology that enables ultra-sensitive, high-throughput and quantitative screening of synaptogenesis. Our platform enables the induction of synaptic structures in regular arrays by precise positioning of non-neuronal cells expressing synaptic proteins, while allowing neurites to grow freely around these cells. The technology increases by tenfold the sensitivity of the traditional assays, and simultaneously decreases the time required to capture synaptogenic events by an order of magnitude. It is readily incorporated into multiwell formats compatible with industrial high-throughput screening platforms. Using this technology, we screened a chemical library, and identified novel histone deacetylase (HDAC) inhibitors that improve neuroligin-1-induced synaptogenesis by modulating class-I HDACs. We also found a structure–activity relationship for designing novel potent histone deacetylase inhibitors, which can be applied towards development of new therapeutics.

Suggested Citation

  • Peng Shi & Mark A. Scott & Balaram Ghosh & Dongpeng Wan & Zachary Wissner-Gross & Ralph Mazitschek & Stephen J. Haggarty & Mehmet Fatih Yanik, 2011. "Synapse microarray identification of small molecules that enhance synaptogenesis," Nature Communications, Nature, vol. 2(1), pages 1-10, September.
    • Handle: RePEc:nat:natcom:v:2:y:2011:i:1:d:10.1038_ncomms1518
    DOI: 10.1038/ncomms1518
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