The human brain consists of approximately 100 billion neurons, which form over 100 trillion synapses with specific targets. How neurons find the correct targets and how the correct wiring of the brain influences behavior are central questions, and the focus of this proposal. The nematode C. elegans offers an excellent model system to explore how synaptic specificity is achieved in vivo, and how correct synaptic choices influence the formation of neuronal circuits, and behavior. AIY, an important interneuron in the C. elegans brain, receives inputs from multiple sensory neurons to modulate behaviors such as thermotaxis, chemotaxis and learning. During development AIY contacts many neurites, but selects only three neurons (RIA, RIB and AIZ) as its postsynaptic partners. The molecular mechanisms used by AIY to discriminate between potential targets and form functional neuronal circuits are not understood. Here I propose to characterize how synaptogenesis is regulated in the complex environment of the C. elegans brain by studying synaptic formation in the thermotaxis neural circuit. A visual forward genetic screen on AIY synapses has yielded multiple mutants with abnormal synaptic patterns. I will identify AIY synaptic specificity molecules by characterizing these mutants. Initial characterization of one class of mutants indicates that immunoglobulin superfamily protein UNC-40/DCC directs AIY synaptogenesis in a cell autonomous manner. In unc-40 mutant, AIY exhibits normal axon trajectory with abnormal presynaptic locations. UNC-40 localizes to AIY presynaptic sites in wild type animals. Furthermore, mislocalization of UNC-40 leads to ectopic presynaptic terminal formation at the location of mislocalized UNC-40. Further experiments will identify the mechanism by which unc-40 directs synaptic target selection in AIY. Future characterization of mutants with similar AIY phenotype as unc-40 will determine the molecular signaling pathway that leads to correct AIY synaptogenesis. Together our work promises to lend us insights into the molecular components that direct correct synaptogenesis in the C. elegans brain. Altered synaptogenesis might lead to a number of neurodevelopmental disorders and human diseases such as schizophrenia and autism. Understanding correct synaptogenesis should provide insights into how functional neuronal circuits are constructed during development and how the correct formation of these circuits affects behavior.
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