How discrete homeostatic signals stabilize synapse function across time

点击翻译按钮获取中文摘要

PROJECT SUMMARY Background and Objectives: Synapses and circuits possess a robust capacity for keeping their outputs stable. Using the Drosophila melanogaster neuromuscular junction (NMJ) as a model synapse, many labs have recently identified dozens of signaling molecules and processes that stabilize synapse function through a non-Hebbian form of homeostatic neuroplasticity called presynaptic homeostatic potentiation (PHP). These findings offer a rich reservoir for discovery science, but at this point we have little understanding of how dozens of discrete homeostatic signaling molecules integrate into coherent system that stabilizes synapse function over time. The objective of this proposal is to solve that problem combining genetics, pharmacology, imaging, biochemistry, and electrophysiology. Ultimately, improved knowledge about homeostatic forms of synaptic plasticity could lead to a better understanding of neurological disorders that occur when synapse stability is lost. Specific Aims and Research Design: This project has two specific aims. We know that PHP at the Drosophila NMJ can be acutely induced in minutes and then chronically maintained for days. The first aim is to define a sequence of events that occurs during the opening minutes of PHP induction. For this aim, we take advantage of a serendipitous finding from a genetic screen: impaired chaperone function in the muscle slows PHP signaling. Using this genetic tool we will delineate an order of processes that occurs as the muscle signals to the nerve and potentiates release. For the second aim, we developed a new pharmacological approach to monitor the transition periods between induction, acute expression, and long-term maintenance of PHP. We will apply this new method to characterize about 25 known genetic conditions that impact the sustained maintenance of PHP. We expect to define distinct PHP signaling modalities. Between our aims, the expected outcome is a model of how a synapse can sustain homeostatic function by integrating multiple signals across phases of time. Health Relatedness: Neurological disorders like epilepsy, ataxia, and migraine are associated with unstable neuronal function. Understanding how synapses work to maintain stability on a molecular level could have pro- found implications for disorders with underlying neuronal instabilities. Yet the signaling events that tightly control levels of synaptic output are poorly understood. The tractable Drosophila NMJ employs homoestatic strategies to stabilize synapse function – such as altering levels of presynaptic calcium influx – that are shared by mammalian central synapses. Taking advantage of the molecular and genetic tools offered by the NMJ promises to shed light on universally conserved mechanisms of how synapses maintain stable function throughout life.