Long-term editing of brain circuits in mice using an engineered electrical synapse

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.