Researchers Engineer Fish Proteins to Create Electrical Synapses in Mammalian Brain Circuits

Electrical signalling between different populations of brain cells supports cognitive and emotional functions. Approaches that can selectively regulate signalling between specific cell types in mammalian neural circuits have been limited. A research paper published by Nature reported the engineering of an electrical synapse using two connexin proteins from white perch fish.

The proteins, connexin 34.7 and connexin 35, were modified through protein mutagenesis. Researchers developed a new in vitro system to test connexin hemichannel docking and used computational modelling to identify a structural motif involved in electrical synapse formation.

Targeting this motif produced hemichannels that dock with each other to form functional electrical synapses but do not interact with major connexins found in the mammalian central nervous system. The engineered synapse was validated in vivo in Caenorhabditis elegans worms and Mus musculus mice.

It strengthened communication across neural circuits made up of distinct cell types and modified the animals' behaviour. The paper establishes a method called long-term integration of circuits using connexins, or LinCx, for precision circuit editing in mammals.

By exploiting protein mutagenesis and computational modelling, the team identified a structural motif contributing to electrical synapse formation. The modified connexin 34.7 and connexin 35 hemichannels were designed to interact only with each other.

This selectivity avoids unintended coupling with the mammalian connexins normally expressed in the central nervous system. The new in vitro assay system allowed direct testing of hemichannel docking. Computational modelling supported the identification of the key motif.

These steps produced a tool that can be expressed in chosen cell populations to create synthetic electrical connections.

Experiments in worms and mice showed that the engineered electrical synapse can strengthen signalling between paired cell types. The resulting changes in circuit function led to corresponding modifications in behaviour. The approach provides a means to edit neural circuits over the long term in mammals.

The paper noted that electrical signalling underpins cognitive and emotional functions. The LinCx method offers a new way to regulate signalling between specific cellular components of a neural circuit. Further development could expand the toolkit available for circuit-level neuroscience research.