PROJECT SUMMARY Retinal neurons establish synaptic connections with specialized functional properties to achieve parallel visual information processing. We recently identified a trans-synaptic mechanism that coordinates the precise alignment between pre-synaptic neurotransmitter release site and post- synaptic receptors complex at retinal photoreceptor synapses. The key organizer for this trans- synaptic complex is α2δ4, a protein traditionally known as the auxiliary subunit of voltage gated calcium channels (VGCCs). We showed that α2δ4 controls photoreceptor synapse formation through regulating VGCC mediated Ca2+ influx and interacting with synaptogenic cell adhesion molecules. Our findings have important relevance to Alzheimer’s Disease (AD), of which the hallmarks are amyloid β (Aβ) deposit and synaptic degeneration. Growing evidence supports that Aβ induces synaptotoxicity through disrupting Ca2+ influx through VGCC which leads to all major molecular and cellular alterations in AD. However, the molecular basis underlying Aβ induced VGCC functional change and the downstream signaling linking VGCC dysfunction to synaptic deficits remain largely unknown. Retinas in AD individuals also have Aβ deposits and display impaired synaptic morphology and function which are associated with cognitive performance, suggesting that synapses in the retina and brain respond to Aβ in a similar fashion and that retinal synapses may provide informative biomarkers for the pathology of AD. However, the molecular mechanism underlying Aβ induced retinal synaptic changes remains virtually unknown. We hypothesize that extracellular α2δ proteins are key mediators for Aβ triggered VGCC dysfunction and that downstream effectors of disrupted VGCC function serve as convergent signaling mechanism underlying synaptic dysfunction in AD. The long-term goal of this proposed study is to uncover the molecular basis of synaptic degeneration in AD and develop mechanism-based clinical interventions. The objective of the proposed work is to study the role of previously identified key synaptic organizer, α2δ4, in AD related retinal synaptic deficit and to identify key signaling pathways underlying synaptic degeneration in AD retina. This proposal is significant in that it has the potential to uncover previously unappreciated and understudied basic biochemical pathways related to AD which will stimulate exciting future AD mechanistic studies.