Project Summary / Abstract Elucidating the molecular mechanisms that respond to membrane voltage changes at neuronal synapses and link these changes to the appropriate cellular responses is critical to physiology, as neural circuitry must maintain homeostasis while adapting to novel conditions, as well as in relation to neurological and neurodegenerative diseases, many of which ultimately result from defective synaptic transmission. Drosophila melanogaster has emerged as a powerful genetic model for dissecting such mechanisms. While significant progress has been made in identifying the structural components of synapses, as well as the molecules used by pre- and postsynaptic cells to communicate across the synaptic cleft, the mechanism by which these cellular processes integrate with transient changes in membrane voltage remain poorly understood. The current proposal will address this knowledge gap by focusing on how a noncanonical localized form bone morphogenetic protein (BMP) signaling at synapses serves as a sensor for membrane voltage, and the potential for this form of signaling to serve as an adapter between transient membrane voltage changes and more stable cellular alterations. We will test three central hypotheses: 1) that local BMP signaling responds to voltage changes at synapses; 2) that synaptic BMP signaling dynamically rises and falls in response to acute changes in membrane voltage; and 3) that synaptic BMP signaling complexes interact with a distinct suite of regulatory and effector molecules. These hypotheses will be tested by using a combination of in vivo genetics, gene editing, immunofluorescent microscopy, electron microscopy, molecular biology, biochemistry, and electrophysiology methods. The short-term impact of these studies will be novel insights into the molecular machinery linking membrane voltage changes with cellular and molecular alterations at Drosophila neuromuscular junction synapses. Ultimately, these studies may identify evolutionary conserved regulatory mechanisms with an important role in synaptic physiology in humans, and potentially contribute to our understanding of how disruptions in these cellular processes underlie the pathophysiology of neurological and neurodegenerative disease states.