Nanophysiology: Bridging synapse ultrastructure, biology, and physiology using scanning ion conductance microscopy

Synaptic communication is at the core of neural circuit function, and its plasticity allows the nervous system to adapt to the changes in its environment. Understanding the mechanisms of this synaptic (re)organization will benefit from novel methodologies that enable simultaneous study of synaptic ultrastructure, biology, and physiology in identified circuits. Here, we describe one of these methodologies, i.e., scanning ion conductance microscopy (SICM), for electrical mapping of the membrane anatomy in tens of nanometers resolution in living neurons. When combined with traditional patch-clamp and fluorescence microscopy techniques, and the newly emerging nanointerference methodologies, SICM has the potential to mechanistically bridge the synaptic structure and function longitudinally throughout the life of a synapse.