Structure and regulation of synaptic architecture

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Structural plasticity contributes to long-lasting alterations in neuronal function during development, as well as in learning and memory, and occurs in response to environmental and activity-dependent signaling cascades. The receptors that transduce these synaptic growth signals are regulated by endocytic recycling, but we do not understand what internal compartments they signal from, what special properties of those compartments enable signaling to occur, and ultimately how the membrane traffic machinery itself can be regulated to control synaptic growth. The intersection of signaling and membrane traffic is particularly intriguing in the presynaptic compartment of neurons, because synapses are highly specialized for both exocytic and endocytic traffic of synaptic vesicles in response to activity. Signaling receptor internalization and the synaptic vesicle cycle use a highly overlapping set of trafficking machinery, but little is understood about cross-talk between these processes and how activity-dependent modes of regulation of trafficking machinery might be used to control signal transduction. This proposal uses a combination of biochemical, genetic, and cell biological approaches in the Drosophila larval neuromuscular junction (NMJ) to unravel the molecular mechanisms by which conserved membraneremodeling proteins respond to extrinsic and intrinsic cues to modify signal transduction, leading to changes in synaptic architecture. The aims of this proposal are (1) to characterize the biochemical activities and interactions of lipid-deforming proteins that control receptor traffic at early endosomes and to evaluate how these proteins work together in vivo; and (2) to obtain 3-dimenslonal high-resolution ultrastructures of presynaptic endosomes at the NMJ, and to determine their relationship to other cellular structures in wildtype and mutant animals. These receptor trafficking events are implicated in neuronal diseases ranging from mental retardation to neurodegenerative disease and addiction, underlining the health importance of understanding how signal transduction is modulated by intracellular membrane traffic in neurons.