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

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

doi:10.1016/j.neuron.2024.08.019

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

Neuron. 2024 Nov 20;112(22):3680-3696.e8. doi: 10.1016/j.neuron.2024.08.019. Epub 2024 Sep 20.

Authors

Yukun A Hao¹, Sungmoo Lee², Richard H Roth³, Silvia Natale⁴, Laura Gomez⁵, Jiannis Taxidis⁶, Philipp S O'Neill⁷, Vincent Villette⁸, Jonathan Bradley⁸, Zeguan Wang⁹, Dongyun Jiang², Guofeng Zhang², Mengjun Sheng³, Di Lu³, Edward Boyden¹⁰, Igor Delvendahl⁷, Peyman Golshani¹¹, Marius Wernig¹², Daniel E Feldman¹³, Na Ji⁵, Jun Ding³, Thomas C Südhof¹⁴, Thomas R Clandinin², Michael Z Lin¹⁵

Affiliations

¹ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
² Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
³ Department of Neurosurgery, Stanford University, Stanford, CA 94305, USA.
⁴ Department of Molecular & Cellular Physiology, Stanford University, Stanford, CA 94305, USA.
⁵ Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA; Department of Physics, University of California Berkeley, CA 94720, USA.
⁶ Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA.
⁷ Department of Molecular Life Sciences, University of Zurich (UZH), 8057 Zurich, Switzerland; Neuroscience Center Zurich, 8057 Zurich, Switzerland.
⁸ Institut de Biologie de l'École Normale Supérieure (IBENS), CNRS, INSERM, PSL Research University, Paris 75005, France.
⁹ Departments of Brain and Cognitive Sciences, Media Arts and Sciences, and Biological Engineering, MIT, Cambridge, MA 02139, USA; McGovern Institute, MIT, Cambridge, MA 02139, USA.
¹⁰ Departments of Brain and Cognitive Sciences, Media Arts and Sciences, and Biological Engineering, MIT, Cambridge, MA 02139, USA; McGovern Institute, MIT, Cambridge, MA 02139, USA; Howard Hughes Medical Institute, Cambridge, MA 02139, USA.
¹¹ Department of Neurology, UCLA David Geffen School of Medicine, Los Angeles, CA 90095, USA; Semel Institute for Neuroscience and Human Behavior, David Geffen School of Medicine, Los Angeles, CA 90095, USA.
¹² Department of Pathology, Stanford University, Stanford, CA 94305, USA.
¹³ Department of Molecular and Cell Biology and Helen Wills Neuroscience Institute, University of California Berkeley, Berkeley, CA 94720, USA.
¹⁴ Department of Molecular & Cellular Physiology, Stanford University, Stanford, CA 94305, USA; Howard Hughes Medical Institute, Stanford University, Stanford, CA 94305, USA.
¹⁵ Department of Bioengineering, Stanford University, Stanford, CA 94305, USA; Department of Neurobiology, Stanford University, Stanford, CA 94305, USA. Electronic address: mzlin@stanford.edu.

PMID: 39305894
PMCID: PMC11581914 (available on 2025-11-20)
DOI: 10.1016/j.neuron.2024.08.019

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.

Keywords: EPSP; GEVI; action potentials; subthreshold activities; voltage imaging.

MeSH terms

Action Potentials* / physiology
Animals
Cells, Cultured
Excitatory Postsynaptic Potentials* / physiology
HEK293 Cells
Humans
Neurons / physiology
Rats
Synapses / physiology

Abstract

MeSH terms

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