Changes in the number, morphology or structure of synaptic connections between neurons in response to alterations in neuronal activity has long been thought to be essential for learning and memory formation and this process is impaired in diseases such as motor neuron disease, autism, epilepsy and Alzheimer's disease. My long-term goal is to understand how the patterns of activity at synapses are integrated with molecular signaling pathways to produce changes in synaptic architecture and to acquire a comprehensive training for a career in neuroscience research. The objective of this application is to determine the signaling pathways required for morphological growth of a Drosophila neuromuscular synapse in response increased motor neuron activity. The Drosophila model system offers a powerful combination of genetic, molecular and cell biology tools combined with stereotyped neuromuscular synapses, highly selective neuronal drivers and accessible electrophysiology. The central hypothesis of this application is that increased neuronal activity can produce expanded synaptic growth by modulating signaling mechanisms also required for the normal morphological development of this synapse, namely Bone Morphogenetic Protein (BMP) proteins, members of the Transforming Growth Factor b (TGF-b) family of cytokines. This hypothesis has been formulated based on strong preliminary data and will be tested it by pursuing two specific aims: 1. Identify the molecular signaling pathways required for activity-dependent synaptic expansion. The approach used to test this hypothesis will be to combine gain-of-function and loss-of-function BMP signaling mutants with mutants that increase neuronal excitability. 2) Establish how neuronal activity can modulate retrograde signaling pathways. The approach used to address this will be to inhibit synaptic release in mutants with increased neuronal excitability using transgenic neurotoxins and other mutants. This research will address a gap in our knowledge about how neuronal activity regulates molecular signaling pathways. These results are expected to have a positive impact, providing a model system to examine how synaptic structure formation might be disrupted in neurological disease and build a foundation for future therapies to ameliorate their devastating effects. ? ? ?
