Synapse microarray identification of small molecules that enhance synaptogenesis

Peng Shi, Mark A. Scott, Balaram Ghosh, Dongpeng Wan, Zachary Wissner-Gross, Ralph Mazitschek, Stephen J. Haggarty and Mehmet Fatih Yanik ()
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Peng Shi: Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.
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
Mehmet Fatih Yanik: Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA.

Nature Communications, 2011, vol. 2, issue 1, 1-10

Abstract: 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.

Date: 2011
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DOI: 10.1038/ncomms1518

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