A fast and responsive voltage indicator with enhanced sensitivity for unitary synaptic events

Neuron 2024

Yukun A. Hao and Sungmoo Lee and Richard H. Roth and Silvia Natale and Laura Gomez and Jiannis Taxidis and Philipp S. O'Neill and Vincent Villette and Jonathan Bradley and Zeguan Wang and Dongyun Jiang and Guofeng Zhang and Mengjun Sheng and Di Lu and Edward Boyden and Igor Delvendahl and Peyman Golshani and Marius Wernig and Daniel E. Feldman and Na Ji and Jun Ding and Thomas C. S{\"u}dhof and Thomas R. Clandinin and Michael Z. Lin

Abstract

A remaining challenge for genetically encoded voltage indicators (GEVIs) is the reliable detection of excitatory postsynaptic potentials (EPSPs). Here, we developed ASAP5 as a GEVI with enhanced activation kinetics and responsivity near resting membrane potentials for improved detection of both spiking and subthreshold activity. ASAP5 reported action potentials (APs) in vivo with higher signal-to-noise ratios than previous GEVIs and successfully detected graded and subthreshold responses to sensory stimuli in single two-photon trials. In cultured rat or human neurons, somatic ASAP5 reported synaptic events propagating centripetally and could detect ∼1-mV EPSPs. By imaging spontaneous EPSPs throughout dendrites, we found that EPSP amplitudes decay exponentially during propagation and that amplitude at the initiation site generally increases with distance from the soma. These results extend the applications of voltage imaging to the quantal response domain, including in human neurons, opening up the possibility of high-throughput, high-content characterization of neuronal dysfunction in disease.

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