Single-Molecule-Resolution Approaches in Synaptic Biology

Synapses between neurons are the primary loci for information transfer and storage in the brain. An individual neuron, alone, can make over 10000 synaptic contacts. It is, however, not easy to investigate what goes on locally within a synapse because many synaptic compartments are only a few hundred nanometers wide in size─close to the diffraction limit of light. To observe the biomolecular machinery and processes within synapses, in situ single-molecule techniques are emerging as powerful tools. Guided by important biological questions, this Perspective will highlight recent advances in using these techniques to obtain in situ measurements of synaptic molecules in three aspects: the cell-biological machinery within synapses, the synaptic architecture, and the synaptic neurotransmitter receptors. These advances showcase the increasing importance of single-molecule-resolution techniques for accessing subcellular biophysical and biomolecular information related to the brain.