Dysbindin-Dependent Synaptic Vesicle Fusion Mechanisms

与人类精神/神经发育障碍相关的基因突变如何从单个分子缺陷逐步扩大到蛋白质网络（相互作用组）、突触生理学和行为？我们寻求这个问题的答案，因为它们在神经发育障碍中具有很好的解释和干预作用。我们选择利用果蝇中反向遗传学的联合力量来解决这个问题，在实验上定义了dysbinding - snare机制的相互作用。我们评估了基因操纵神经发育障碍途径的机制和表型后果，该途径由非结合NSF和snre依赖的囊泡融合构成。在本应用中，我们将确定基因干扰失调结合蛋白- snare融合机制对果蝇NMJ突触生理学和两种形式的突触可塑性的功能后果：突触前稳态可塑性和一种简单的学习形式，短期嗅觉习惯化。我们假设，突触前核内体囊泡运输是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.