High Throughput Screen for Small Molecule Probes for Neural Network Development

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DESCRIPTION (provided by applicant): Many major neurodevelopmental disorders, including autism, epilepsy and schizophrenia, are believed to the caused by aberrant synapse formation during brain development, resulting in an excess or deficit of certain classes of synapses. Our long term goal is to understand the molecular mechanisms of synapse formation in the central nervous system (CNS), with the aim of developing therapeutics for these devastating diseases. The process of synapse formation has been best characterized in the peripheral nervous system, where the complete loss of neuromuscular junctions has been reported for multiple single gene knockout mice. In the central nervous system, despite the presence of many proteins that show strong synaptogenic activity in vitro, genetic deletion of several of these proteins result in only subtle changes in synapse density limited to small populations of neurons. These results suggest that the synaptogenic machinery in the CNS is heavily redundant; a situation that makes it inefficient to apply traditional genetic approaches to study the problem. We believe that an unbiased chemical screen for determinants of synapse formation, with its potential to block or enhance key pathways and entire classes of genes, may present a more efficient approach to studying synaptogenic mechanisms in the CNS. In addition, the study may also generate small molecule probes that will be useful in perturbing synapse formation and excitatory-inhibitory balance in vivo. An excess or deficit of specific synapses has been hypothesized to underlie many neurodevelopmental disorders, but to date, these hypotheses have been difficult to prove due to the lack of tools to perturb the underlying network connectivity. We believe our proposal will remedy this situation, and at the same time generate a high impact dataset which will shed light on the mechanisms of synapse formation in the CNS.