Dysbindin-Dependent Synaptic Vesicle Fusion Mechanisms

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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.