Genetically Encoded Voltage Indicators Are Illuminating Subcellular Physiology of the Axon

Everything we see and do is regulated by electrical signals in our nerves and muscle. Ion channels are crucial for sensing and generating electrical signals. Two voltage-dependent conductances, Na⁺ and K⁺, form the bedrock of the electrical impulse in the brain known as the action potential. Several classes of mammalian neurons express combinations of nearly 100 different varieties of these two voltage-dependent channels and their subunits. Not surprisingly, this variability orchestrates a diversity of action potential shapes and firing patterns that have been studied in detail at neural somata. A remarkably understudied phenomena exists in subcellular compartments of the axon, where action potentials initiate synaptic transmission. Ion channel research was catalyzed by the invention of glass electrodes to measure electrical signals in cell membranes, however, progress in the field of neurobiology has been stymied by the fact that most axons in the mammalian CNS are far too small and delicate for measuring ion channel function with electrodes. These quantitative measurements of membrane voltage can be achieved within the axon using light. A revolution of optical voltage sensors has enabled exploring important questions of how ion channels regulate axon physiology and synaptic transmission. In this review we will consider advantages and disadvantages of different fluorescent voltage indicators and discuss particularly relevant questions that these indicators can elucidate for understanding the crucial relationship between action potentials and synaptic transmission.