The refinement of neuronal circuits requires both a stabilization of existing synaptic connections and a disassembly of previously functional synapses. While the mechanisms of synapse formation have been extensively studied, very little is known about the molecular mechanisms that are responsible for the stabilization of synaptic connections. Any inappropriate loss of synaptic stability will lead to disruptions of neuronal circuits and finally to neurodegenerative disease. Therefore, the identification of the molecular mechanisms that regulate synapse stability versus disassembly may help to understand how synaptic circuits are modified in response to signaling events and may provide useful insights towards our understanding of neurodegenerative disease. I am combining the advantages of Drosophila genetics, cell biology and physiology with a high-resolution assay for synapse retraction to identify and characterize genes involved in synapse formation, stability and disassembly. My postdoctoral work has highlighted the importance of a presynaptic cytoskeletal network that links cell adhesion molecules to the underlying actin and microtubule cytoskeleton to achieve normal synapse formation and stability. Here I propose to define the signaling systems that control the assembly and stability of the presynaptic network during synapse formation and maintenance. In the first aim I will focus on the adaptor molecule Ankyrin2 that has the potential to directly link synaptic cell adhesion molecules to the presynaptic microtubule cytoskeleton. The second aim addresses how actin dynamics contribute to normal synapse formation and stability. Finally, I will use forward genetic approaches to identify novel molecules required for synaptic stability. Together these projects will provide insights into the molecular mechanisms that regulate synapse stability in response to intrinsic and extrinsic signaling systems within neuronal circuits.