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

ABSTRACT 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. Synapse, 69:233–241, 2015. © 2015 Wiley Periodicals, Inc. Contact‐free scanning probe microscopy techniques allow longitudinal visualization of living synapses and neural compartments in nanometer resolution; figure on the left exemplifies the surface reconstruction capabilities of scanning ion conductance microscopy (SICM) in hippocampal neurons. This review by Scheenen and Celikel provides a critical insight on the recent developments in SICM, and highlight the potential synergy among emerging (super‐resolution) techniques for mechanistic understanding of structure and function relationship in synapses.