Abstract: Age related hearing loss (ARHL) has a major impact on quality of life of more than 70% of those over the age of 70. It is a growing problem with significant socioeconomic ramifications. The cause of ARHL is complex and likely involves both environmental and genetic factors. Symptoms associated with ARHL, specifically, the initial loss of ability to discriminate sound in a noisy environment that progress to high frequency loss that can further progress to lower frequencies over time, suggest a common vulnerability that is independent of the initial trigger. We are postulating that common to ARHL is an initial loss of hair cell afferent fiber synapses. Much as with noise induced hearing loss, we hypothesize a selective loss of high threshold fibers. We will test these hypotheses using multiple genetic mouse models of ARHL. Each will be monitored using whole animal auditory testing including auditory brainstem responses and distortion product otoacoustic emissions to document the time course of onset of ARHL in each model. Specific Aim 2 will evaluate synaptic maintenance and proteins associated with pre and postsynaptic elements to further characterize the temporal windows associated with hearing loss. Specific Aim 3 will use electrophysiological and optical technologies to measure synaptic vesicle release and trafficking, monitor calcium homeostasis and record postsynaptic properties synaptic potentials as well as electrical properties. Each aim is well integrated with the goals and techniques available from each of the other investigators on this proposal and together we shall identify a global framework in which to address this important translational problem.