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Designer indicators for two-photon recording of subthreshold voltage dynamics
Michelle A Land1, Mario Galdamez1, Vincent Villette2
1Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
Nature Methods
|April 15, 2026
Summary
New JEDI3 indicators enable sensitive in vivo measurement of neuronal subthreshold voltage dynamics using two-photon microscopy. This breakthrough allows detailed study of neural circuits and information processing in the brain.
Area of Science:
- Neuroscience
- Molecular Biology
- Biophysics
Background:
- Subthreshold voltage dynamics are crucial for neuronal function but difficult to measure in vivo.
- Existing genetically encoded voltage indicators lack sensitivity for millivolt-scale fluctuations with two-photon microscopy.
Purpose of the Study:
- To engineer genetically encoded voltage indicators with enhanced sensitivity for subthreshold voltage dynamics.
- To enable in vivo, deep-tissue optical recording of millivolt-scale neuronal voltage changes.
Main Methods:
- Engineering of JEDI3sub and JEDI3hyp genetically encoded voltage indicators.
- Two-photon microscopy for in vivo imaging in mouse brain.
- Recording of subthreshold voltage dynamics in various neuronal populations and structures.
Main Results:
- JEDI3sub allowed simultaneous tracking of subthreshold optical tuning in over 100 cells.
- JEDI3hyp captured subthreshold dynamics in hippocampal PV+ interneurons during sharp-wave ripples.
- JEDI3hyp enabled prolonged imaging of millivolt-scale voltage changes in deep-layer neurons and dendrites.
Conclusions:
- JEDI3 indicators significantly enhance the sensitivity of two-photon microscopy for subthreshold voltage dynamics.
- These indicators provide novel tools for dissecting neural information processing in health and disease.
- Opens new research avenues for understanding brain function at the subthreshold level.
