Project Summary Although much is known regarding the development of synapses, very little is known about how these complex structures are maintained throughout the aging process. Defects in synaptic communication are responsible for a great number of neurological disorders, and they are associated with the earliest stages of several neurodegenerative diseases. A major hurdle in the field has been the lack of a genetically tractable model system in which to systematically assess synaptic dysfunction over time in vivo. To address this issue, we propose to use Drosophila to examine the structural and functional impairment of synaptic integrity with aging in adult flight muscles. Our guiding hypothesis is that maintaining synaptic structure and function requires a conserved set of genes involved in trans-synaptic signaling, and that disruption of these signaling pathways are among the early deficits in neurological disorders. To test this hypothesis, we propose to pursue three Specific Aims. The first Aim is to identify the mechanisms underlying synaptic dysfunction in mayday mutants, which we previously identified as displaying age-dependent denervation of flight motor neurons. Our second aim is to characterize novel genes associated with synaptic impairment that we identified through a genome-wide screen. Our third Aim is to determine the structural and functional impairment of synapses in a model of Amyotrophic Lateral Sclerosis (ALS). Our proposed research has the potential to reveal the cellular and molecular mechanisms responsible for maintaining synaptic integrity with age, many of which will likely serve as potential therapeutic targets for developing treatment strategies for several neurological disorders.