Technology Development Initiative – Paper of the Month – December 2024

The graphical abstract from this study. Image copyright Elsevier.

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

Published in Neuron.

Authors

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

Paper presented by Dr. Zilu Ma and selected by the NIDA TDI Paper of the Month Committee

Publication Brief Description

Unitary single synaptic transmission events are essential for information processing in the healthy brain and are a sensitive sign of synaptic dysfunction in disease such as autism spectrum disorder and schizophrenia. Miniature excitatory postsynaptic potentials or currents (mEPSP or mEPSC) have mostly been measured using patch-clamp electrophysiology, which is low throughput in nature. In the past decade, development in genetically encoded voltage indicators (GEVIs) has dramatically improved single-trial imaging of spikes and subthreshold events. However, reliable detection of mEPSPs still remains challenging and this paper introduces ASAP5, a GEVI with faster and steeper fluorescence response to changes in membrane potential than its predecessors. ASAP5 exhibits a steeper fluorescence response to changes in membrane potential and two folds of amplitude with similar brightness than other GEIVs. ASAP5 enables high-throughput imaging of mEPSP and reveals its dendritic propagation and network activity in cultured rodent and human neurons. In addition, in-vivo studies using awake mice and fruit flies during behavior and sensory stimulation demonstrates ASAP5’s utility in various species and across imaging platforms (one-photon and two-photon microscopy) and showcases its   versatily for studying neural dynamics in vivo and in vitro. The ability of ASAP5 to detect single-trial spikes and subthreshold changes in membrane potential bridges the gap between low-throughput electrophysiology and non-invasive imaging, making it a valuable resource for investigating synaptic dysfunction in neurodevelopmental and neurodegenerative diseases.

@article{pmid39305894,

title = {A fast and responsive voltage indicator with enhanced sensitivity for unitary synaptic events},

author = {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 Südhof and Thomas R Clandinin and Michael Z Lin},

url = {https://pubmed.ncbi.nlm.nih.gov/39305894/},

doi = {10.1016/j.neuron.2024.08.019},

issn = {1097-4199},

year  = {2024},

date = {2024-11-01},

urldate = {2024-11-01},

journal = {Neuron},

volume = {112},

number = {22},

pages = {3680--3696.e8},

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 = {},

pubstate = {published},

tppubtype = {article}

}