Designer electrical synapses enable long-term, cell-type-specific circuit editing in mammals
A team engineered a heterotypic electrical synapse using Morone americana connexins Cx34.7 and Cx35 (Cx34.7(M1)–Cx35(M1)) that dock exclusively with each other and not with endogenous mammalian connexins. They developed FETCH to screen docking compatibility, used computational modeling to design docking-specific mutants, and demonstrated functional, selective coupling in vitro and in vivo. In C. elegans, the designer synapse recoded a thermotaxis circuit similarly to native Cx36–Cx36 connections; in mice, targeted LinCx editing between PYR neurons and PV+ interneurons in the prefrontal cortex enhanced theta–HFO coupling and altered neuronal dynamics and social/exploratory behaviors. This work establishes a platform for durable, precise circuit modification with potential therapeutic applications.