Long-term editing of brain circuits using an engineered electrical synapse
14 affiliations
- 1Deparment of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA
- 2Howard Hughes Medical Institute, Chevy Chase, MD, USA
- 3Department of Neurobiology, Duke University Medical Center, Durham, NC, USA
- 4Department of Neuroscience and Department of Cell Biology, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, CT, USA
- 5Department of Biomedical Engineering, Duke University, Durham, NC, USA
- 6Salk Institute for Biological Studies, La Jolla, CA, USA
- 7Department of Neuroscience, University of Connecticut School of Medicine, Farmington, CT, USA
- 8Instituto de Neurobiología, Recinto de Ciencias Médicas, Universidad de Puerto Rico, San Juan, Puerto Rico
- 9Department of Molecular Physiology and Biophysics, Department of Psychiatry, University of Iowa, Iowa City, IA, USA
- 10Deparment of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, NC, USA. [email protected]
- 11Department of Biomedical Engineering, Duke University, Durham, NC, USA. [email protected]
- 12Department of Neurobiology, Duke University Medical Center, Durham, NC, USA. [email protected]
- 13Department of Neurosurgery, Duke University Medical Center, Durham, NC, USA. [email protected]
- 14Howard Hughes Medical Institute, Chevy Chase, MD, USA. [email protected]
Abstract
Electrical signaling across distinct populations of brain cells underpins cognitive and emotional function; however, approaches that selectively regulate electrical signaling between two cellular components of a mammalian neural circuit remain sparse. Here, we engineered an electrical synapse composed of two connexin proteins found in Morone americana (white perch fish) – connexin34.7 and connexin35 – to accomplish mammalian circuit modulation. By exploiting protein mutagenesis, devising a new in vitro system for assaying connexin hemichannel docking, and performing computational modeling of hemichannel interactions, we uncovered a structural motif that contributes to electrical synapse formation. Targeting these motifs, we designed connexin34.7 and connexin35 hemichannels that dock with each other to form an electrical synapse, but not with other major connexins expressed in the mammalian central nervous system. We validated this electrical synapse in vivo using C. elegans and mice, demonstrating that it can strengthen communication across neural circuits composed of pairs of distinct cell types and modify behavior accordingly. Thus, we establish ‘ L ong-term in tegration of C ircuits using conne x ins’ (LinCx) for precision circuit-editing in mammals.
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BibTeX
@article{ransey2026longterm,
title = {{Long-term editing of brain circuits using an engineered electrical synapse}},
author = {Elizabeth Ransey and Gwenaëlle E. Thomas and Elias M. Wisdom and Agustin Almoril-Porras and Ryan Bowman and Elise Adamson and Kathryn K. Walder-Christensen and Jesse A White and Dalton N. Hughes and Hannah T. Schwennesen and Caly Ferguson and Kay M. Tye and Stephen D. Mague and Longgang Niu and Zhao‐Wen Wang and Daniel Colón-Ramos and Rainbo C. Hultman and Nenad Bursac and Kafui Dzirasa},
journal = {Nature},
year = {2026},
month = may,
doi = {10.1038/s41586-026-10501-y},
url = {https://doi.org/10.1038/s41586-026-10501-y},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - Long-term editing of brain circuits using an engineered electrical synapse
AU - Elizabeth Ransey
AU - Gwenaëlle E. Thomas
AU - Elias M. Wisdom
AU - Agustin Almoril-Porras
AU - Ryan Bowman
AU - Elise Adamson
AU - Kathryn K. Walder-Christensen
AU - Jesse A White
AU - Dalton N. Hughes
AU - Hannah T. Schwennesen
AU - Caly Ferguson
AU - Kay M. Tye
AU - Stephen D. Mague
AU - Longgang Niu
AU - Zhao‐Wen Wang
AU - Daniel Colón-Ramos
AU - Rainbo C. Hultman
AU - Nenad Bursac
AU - Kafui Dzirasa
PY - 2026
DA - 2026/05/13
JO - Nature
DO - 10.1038/s41586-026-10501-y
UR - https://doi.org/10.1038/s41586-026-10501-y
AB - Electrical signaling across distinct populations of brain cells underpins cognitive and emotional function; however, approaches that selectively regulate electrical signaling between two cellular components of a mammalian neural circuit remain sparse. Here, we engineered an electrical synapse composed of two connexin proteins found in Morone americana (white perch fish) – connexin34.7 and connexin35 – to accomplish mammalian circuit modulation. By exploiting protein mutagenesis, devising a new in vitro system for assaying connexin hemichannel docking, and performing computational modeling of hemichannel interactions, we uncovered a structural motif that contributes to electrical synapse formation. Targeting these motifs, we designed connexin34.7 and connexin35 hemichannels that dock with each other to form an electrical synapse, but not with other major connexins expressed in the mammalian central nervous system. We validated this electrical synapse in vivo using C. elegans and mice, demonstrating that it can strengthen communication across neural circuits composed of pairs of distinct cell types and modify behavior accordingly. Thus, we establish ‘ L ong-term in tegration of C ircuits using conne x ins’ (LinCx) for precision circuit-editing in mammals.
SN - 0028-0836
SN - 1476-4687
ER -