The Development and Organization of Central Synapses in Drosophila

描述（申请人提供）：记忆、行为和认知的所有方面都依赖于神经元之间的突触连接。要开始理解神经功能，首先必须理解突触本身：它们是如何组织的，它们的发育和功能所必需的分子机制是什么，来自一种神经元的突触如何与来自其他神经元类别的突触相互作用？本研究旨在通过确定黑腹果蝇中央脑突触的组织、突触维持和发育所需的分子以及不同神经元突触如何相互作用来解决这些问题。在果蝇的嗅觉系统中，三种类型的神经元相互合作，以实现对来自环境的气味的强大感知，处理这些气味，并将信息传递给更高的大脑中心。因此，嗅觉系统为研究单个神经元或神经元群之间具有单细胞分辨率和刻板印象的遗传可及系统提供了机会。我发展了研究嗅觉系统突触组织的方法，建立了一个新的中枢突触模型。这些方法揭示了果蝇触角叶嗅觉神经元突触组织的新方面。这一提议将进一步推动这项工作，提供对单个嗅觉神经元突触的高分辨率分析。它将决定这些突触何时发育，以及发育中的突触与成熟嗅觉神经元的突触有何不同。这样的分析将提供一个基本的框架，从中解决病理条件，包括神经发育障碍，如何改变突触的组织。此外，我将使用这个新的突触模型来检查三类分子，神经神经蛋白、神经毒素和神经球蛋白，它们与智力残疾和自闭症谱系障碍有关。了解这些实体如何促进突触组织对于深入了解这些疾病的基础至关重要。最后，我将研究回路中不同神经元的突触是如何相互关联的。神经回路中神经元之间的协调对其功能和机体行为至关重要。但是电路是如何在突触水平上实现这种协调的，在很大程度上是未知的。使用新建立的方法，我将询问如何干扰回路中一类神经元的突触影响其他神经元的突触。具体来说，我将确定回路如何处理一种特定类型突触的增加和减少，以及回路中的化学突触如何对电突触的损失做出反应。对这些电路反应机制的进一步研究将揭示负责其构建的新分子和组织范式。通过了解单个突触和突触群之间组织的这些方面，我们不仅可以深入了解神经元的功能，还可以深入了解神经回路如何协调信息以确保在生物体水平上发挥适当的功能。

DESCRIPTION (provided by applicant): All aspects of memory, behavior, and cognition rely on the synaptic connections between neurons. To begin to understand neural function, the synapses themselves must first be understood: how are they organized, what are the molecular mechanisms necessary for their development and function, and how do synapses from one type of neuron interact with the synapses from other neuronal classes? This proposal aims to address these questions by determining the organization of synapses in the central brain of Drosophila melanogaster, the molecules necessary for their maintenance and development, and how synapses of different neurons interact. In the Drosophila olfactory system, three neuronal classes cooperate to enable robust sensing of odors from the environment, processing of these odors, and transmission of the information to higher brain centers. The olfactory system thus represents an opportunity to study a genetically accessible system with single-cell resolution and stereotypy within single neurons or between groups of neurons. I have developed methods to study synapse organization in the olfactory system, establishing a new model central synapse. These methods have revealed new aspects of synaptic organization in olfactory neurons in the Drosophila antennal lobe. This proposal will further this work, providing a high-resolution analysis of synapses in single olfactory neurons. It will determine when these synapses develop and how the developing synapse differs from that of the mature olfactory neuron. Such analyses will provide an essential framework from which to address how pathological conditions, including neurodevelopmental disorders, can alter synapse organization. Further, I will use this new model synapse to examine three classes of molecules, the Teneurins, Neurexins and Neuroligins, which are linked to intellectual disabilities and autism spectrum disorders. Understanding how each of these entities contributes to synapse organization is essential for gaining insight into the bases of these disorders. Finally, I will investigate how the synapses of different neurons within a circuit are interrelated. Coordination among neurons in a circuit is essential for its function and organismal behavior. But how a circuit achieves this coordination on a synaptic level is largely unknown. Using newly established methods, I will ask how perturbing the synapses of one neuronal class within a circuit affect synapses of the other neurons. Specifically, I will determine how a circuit deals wih synapse increase and reduction in one specific type, and how chemical synapses within a circuit respond to the loss of electrical synapses. Further study of the mechanisms underlying these circuit responses will unveil new molecules and organizational paradigms responsible for their construction. By understanding these aspects of organization for individual synapses and between groups of synapses, we will gain considerable insight into not just neuronal function, but into how a neural circuit coordinates information to ensure proper function at the organism level.