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

描述（由申请人提供）： 人类大脑由大约1000亿个神经元组成，这些神经元与特定目标形成超过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布线如何影响行为是核心问题，也是本提案的焦点。线虫C. elegans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回路的形成和行为。AIY是C.线虫的大脑接受来自多个感觉神经元的输入，以调节诸如趋热性、趋化性和学习的行为。在发育过程中，AIY接触许多神经突，但只选择三个神经元（RIA，RIB和AIZ）作为其突触后伙伴。AIY用于区分潜在靶点和形成功能性神经回路的分子机制尚不清楚。在这里，我提出的特点是如何突触是在复杂的环境中调节的C。通过研究趋热性神经回路中的突触形成来研究elegans大脑。对AIY突触的视觉遗传筛查已经产生了多个具有异常突触模式的突变体。我将通过描述这些突变体来识别AIY突触特异性分子。一类突变体的初步表征表明，免疫球蛋白超家族蛋白<$A-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。在野生型动物中，AIY-40定位于AIY突触前位点。此外，定位错误的α-40导致在定位错误的α-40的位置形成异位突触前末梢。进一步的实验将确定unc-40在AIY中指导突触靶选择的机制。未来对与unc-40具有类似AIY表型的突变体的表征将确定导致正确AIY突触发生的分子信号传导途径。我们的工作有望帮助我们深入了解在C。优雅的大脑突触发生的改变可能导致许多神经发育障碍和人类疾病，如精神分裂症和自闭症。了解正确的突触发生应该提供深入了解功能性神经元回路在发育过程中是如何构建的，以及这些回路的正确形成如何影响行为。

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.