Synaptic target selection in the thermotaxis neural circuit of C. elegans

描述(由申请人提供)： 人脑由大约1000亿个神经元组成，这些神经元与特定的靶点形成超过100万亿个突触。神经元如何找到正确的目标，以及大脑的正确连接如何影响行为是中心问题，也是这项提议的重点。线虫线虫提供了一个很好的模型系统来探索突触特异性是如何在体内实现的，以及正确的突触选择如何影响神经元电路的形成和行为。AIY是线虫大脑中一个重要的中间神经元，它接受来自多个感觉神经元的输入，调节趋热、趋化和学习等行为。在发育过程中，AIY接触了许多突触，但只选择了三个神经元(RIA、RIB和AIZ)作为突触后伙伴。AIY用于区分潜在靶点和形成功能神经元回路的分子机制尚不清楚。在这里，我建议通过研究趋热神经回路中的突触形成来表征在线虫大脑的复杂环境中突触发生是如何被调节的。AIY突触上的可视正向遗传屏幕已经产生了多个突触模式异常的突变体。我将通过鉴定这些突变体来鉴定AIY突触特异性分子。对一类突变体的初步鉴定表明，免疫球蛋白超家族蛋白UNC-40/DCC以细胞自主的方式指导AIY突触发生。在UNC-40突变体中，AIY表现出正常的轴突轨迹和异常的突触前位置。UNC-40定位于野生型动物的AIY突触前部位。此外，UNC-40的错位定位导致在错位的UNC-40位置异位形成突触前终末。进一步的实验将确定UNC-40指导AIY突触靶点选择的机制。未来与UNC-40具有相似AIY表型的突变体的特征将决定导致正确的AIY突触发生的分子信号通路。我们的工作有望让我们深入了解线虫大脑中指导正确突触发生的分子成分。突触发生改变可能会导致一些神经发育障碍和人类疾病，如精神分裂症和自闭症。理解正确的突触发生应该为在发育过程中如何构建功能神经元电路以及这些电路的正确形成如何影响行为提供见解。

DESCRIPTION (provided by applicant): 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.