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.
Defects in brain development leading to an excess or deficit of synapses may result in neurodevelopmental disorders such as autism, schizophrenia, epilepsy and mental retardation. Currently, no drug exists to directly target the development of synapses in the brain. We propose to screen a large chemical library for compounds that will modulate synapse development in the intact brain, and thereby shed light on the molecular mechanisms of the process as well as provide candidate compounds for both investigative and therapeutic purposes.
|Sia, G M; Clem, R L; Huganir, R L (2013) The human language-associated gene SRPX2 regulates synapse formation and vocalization in mice. Science 342:987-91|
|Sharma, Kamal; Choi, Se-Young; Zhang, Yong et al. (2013) High-throughput genetic screen for synaptogenic factors: identification of LRP6 as critical for excitatory synapse development. Cell Rep 5:1330-41|