The long-term objective of this proposal is to define the role of the postsynaptic cell in the regulation of synaptic development. The general strategy is to combine genetic, molecular, anatomical, and electrophysiological analysis in Drosophila to identify mechanisms by which postsynaptic cells shape the developing synapse. Recent evidence at the Drosophila neuromuscular junction demonstrates that postsynaptic dysfunction leads to a compensatory increase in presynaptic neurotransmitter release. This proposal investigates the hypothesis that postsynaptic activity controls a homeostatic signaling mechanism that regulates presynaptic function. Such homeostatic mechanisms can regulate synaptic activity during development and may compensate for synapse loss following injury or disease. This proposal will investigate the mechanism of the homeostatic response and characterize molecules that regulate the homeostatic, retrograde signaling pathway. Spatial and temporal requirements for homeostatic signaling will be investigated and the presynaptic change underlying homeostatic compensation will be determined. Postsynaptic glutamate receptors play a central role in regulating homeostasis. A novel glutamate receptor has been identified and mutations in this gene have been isolated. This receptor's role in regulating homeostasis will be investigated. In addition, a structure/function analysis of glutamate receptors will be undertaken to determine how they regulate homeostasis. Finally, two novel mutations have been identified that regulate homeostatic and retrograde signaling. These enhancers will be characterized to elucidate their role in the homeostasis pathway. These studies seek to define the mechanisms and molecules that underlie synaptic homeostasis, which is a necessary prerequisite for understanding the role of homeostasis in development and disease.