Millisecond-timescale imaging of the activity of genetically targeted neuronal populations in animals promises considerable leaps forward in our understanding of the brain and behavior, but challenges in its implementation remain. Abdelfattah et al. improve upon the properties of a rhodopsin-based fluorescent genetically encoded voltage indicator, called Voltron, by high-throughput screening of mutant variants in dissociated neurons. A new variant, Votron2, showed enhanced sensitivity to subthreshold potential changes and spiking with the fast kinetics of its predecessor. Voltron2 could be used in acute brain slices to image postsynaptic potentials with greater sensitivity than Voltron, and could be combined with optogenetic actuators for ‘all-optical’ electrophysiology. Encouragingly, in vivo voltage imaging in fish and flies showed higher sensitivity and signal-to-noise ratio with Voltron2 than with Voltron. Voltron2 was also used for in vivo voltage imaging in the mouse hippocampus and cortex and could read out synchronized spiking of parvalbumin-positive hippocampal interneurons, probably driven by subthreshold co-depolarization. Further improvements in the performance of genetically encoded voltage indicators in the brain are likely to continue to spark the neuroscientific quest for understanding.
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