Nature paper engineers fish-derived connexin proteins (Cx34.7/Cx35) into a synthetic electrical synapse for precision mammalian neural circuit editing without off-target gap junctions.
Key Takeaways
Paper introduces LinCx (Long-term Integration of circuits using Connexins), using white perch (Morone americana) connexins Cx34.7 and Cx35 to form exclusively heterotypic electrical synapses in mammals.
Key problem solved: endogenous mammalian connexins form homotypic gap junctions causing off-target circuit coupling; the engineered pair docks only with each other, not with CNS connexins.
Authors developed FETCH (Flow-Enabled Tracking of Connexosomes in HEK293FT cells), a new in vitro assay to screen connexin hemichannel docking compatibility via fluorescence exchange and flow cytometry.
Mutagenesis of extracellular loops EL1 and EL2 across ~70 variants at 16 positions identified mutant pairs (e.g., Cx34.7(K222Q) with Cx35(E224H)) with exclusively heterotypic docking.
Validated in vivo in both C. elegans and mice, demonstrating strengthened cross-circuit communication and measurable behavioral modification.
