We have used a variety of new methods to study the molecular architecture that gives single synapses their individual strength and their unique ability to undergo functional plasticity.

By measuring the fluorescence arising from single vesicles fusing with the presynaptic membrane, we could localize where, even within the tiny bounds of one active zone, that fusion actually takes place. We couldn’t help but call this method “pHluorin for uncovering the site of exocytosis” or pHuse. This should be an invaluable addition to our technical arsenal for dissecting presynaptic molecular mechanisms. pHuse shows that release evoked by action potentials turns out to most frequently arise in only a subregion of the active zone, in areas where the release-priming protein RIM is enriched in distinctive nanoclusters.

By localizing key molecules like RIM in the active zone at the same time as receptors and other molecules in the associated postsynaptic spine, we have identified a new component of synapse architecture. That is, proteins guiding release align with stunning precision to sites of clustered receptors in the postsynaptic membrane. By mapping several aligned proteins, we deduced the presence of a molecular “nanocolumn” that spans the two cells and integrates deep into the postsynaptic density, we believe ultimately engaging with the spine actin cytoskeleton.

Please read the original paper at http://dx.doi.org/10.1038/nature19058.
Read the News and Views from Sigrist and Petzoldt at http://www.nature.com/nature/journal/vaop/ncurrent/full/nature18917.html.