Molecular Configuration, Regulation and Function of Heterochannel Electrical Synapses

Neuron-specific expression of particular gap junction channel components defines the configuration and functional properties of electrical synapses. However, how a neuron utilises multiple, simultaneously expressed channel proteins - connexins or innexins -to make meaningful connections with distinct synaptic partners remains largely unknown. Using the posterior mechanosensory circuit in C. elegans, we discovered that individual electrical synapses can be formed by clustering together molecularly distinct gap junction channel-types made of three different innexin proteins, INX-1, UNC-7, and UNC-9. In this previously unknown configuration, which we term as heterochannel synapses, molecularly distinct gap junction channel types functionally collaborate to regulate posterior touch sensory behaviour, enhancing functional robustness. We show that the synaptic trafficking of the molecularly different channel types within a heterochannel synapse is independently regulated by discrete and conserved kinesin motor proteins, while distinct molecular pathways involving channel-specific retrograde kinesins regulate their turnover. These independent, channel-specific regulations also make individual synapse-level alterations in the composition of heterochannel synapses possible under altered environmental conditions, providing a novel mechanism for electrical synapse plasticity. Finally, we present evidence of heterochannel electrical synapses in C. elegans locomotory circuits and in the cerebellar Purkinje neurons of zebrafish larvae. Altogether, we demonstrate a novel heterochannel organization of electrical synapses, their regulation, and functional importance, which may be a conserved feature of metazoan nervous system.