Dysbindin-Dependent Synaptic Vesicle Fusion Mechanisms

与人类精神/神经发育障碍有关的基因突变是如何从单个分子缺陷逐渐扩大到蛋白质网络(交互作用组)、突触的生理和行为的？我们寻求这个问题的答案，因为它们在神经发育障碍中拥有有希望的解释性和干预性力量。我们选择在果蝇中使用反向遗传学的综合力量来解决这个问题，这是一种实验定义的结合障碍-陷阱机制相互作用。我们评估了基因操作神经发育障碍途径的机制和表型后果，该途径由障碍结合蛋白、NSF依赖和圈套依赖的囊泡融合构成。在这项应用中，我们将确定基因扰动的结合障碍-陷阱融合机制对果蝇NMJ突触的生理学和两种形式的突触可塑性的功能后果：突触前的稳态可塑性和一种简单的学习形式，短期嗅觉习服。我们推测，异常结合蛋白-陷阱机制的相互作用是突触前内体囊泡运输建立突触前内稳态可塑性和嗅觉习惯化所必需的。

How do mutations in genes implicated in human mental/neurodevelopmental disorders progressively scale up from a single molecular defect to protein networks (interactome), the physiology of the synapse, and behavior? We seek answers to this question as they hold promising explanatory and interventional power in neurodevelopmental disorders. We have chosen to address this question using the combined power of reverse genetics in Drosophila, on an experimentally defined dysbindin-SNARE machinery interaction. We evaluate mechanisms and phenotypic consequences of genetically manipulating the neurodevelopmental disorder pathway constituted by dysbindin NSF- and SNARE-dependent vesicle fusion. In this application, we will determine the functional consequences of genetically perturbing dysbindin-SNARE fusion mechanisms on the physiology of the Drosophila NMJ synapse and two forms of synaptic plasticity: presynaptic homeostatic plasticity and a simple form of learning, short-term olfactory habituation. We postulate that the dysbindin-SNARE machinery interactions are necessary for presynaptic endosome vesicle traffic to establish presynaptic homeostatic plasticity and olfactory habituation.