All actions, memory, behavior, and basic functions rely on signal transmission between neurons. In neuronal circuits, synapses represent the fundamental conserved units facilitating neuronal communications. Many pairwise interactions of proteins across the synaptic cleft have been identified, but how the different proteins organize to promote synapse function is not understood. We aim to define the extracellular architecture of the synapse in health and disease using a multipronged structural, biophysical and biochemical approach.