RT Journal Article SR Electronic T1 Electrical synaptic transmission requires a postsynaptic scaffolding protein JF bioRxiv FD Cold Spring Harbor Laboratory SP 2020.12.03.410696 DO 10.1101/2020.12.03.410696 A1 Abagael M. Lasseigne A1 Fabio A. Echeverry A1 Sundas Ijaz A1 Jennifer Carlisle Michel A1 E. Anne Martin A1 Audrey J. Marsh A1 Elisa Trujillo A1 Kurt C. Marsden A1 Alberto E. Pereda A1 Adam C. Miller YR 2020 UL http://biorxiv.org/content/early/2020/12/04/2020.12.03.410696.abstract AB Electrical synaptic transmission relies on neuronal gap junctions containing channels constructed by Connexins. While at chemical synapses neurotransmitter-gated ion channels are critically supported by scaffolding proteins, it is unknown if channels at electrical synapses require similar scaffold support. Here we investigated the functional relationship between neuronal Connexins and Zonula Occludens 1 (ZO1), an intracellular scaffolding protein localized to electrical synapses. Using model electrical synapses in zebrafish Mauthner cells, we demonstrated that ZO1 is required for robust synaptic Connexin localization, but Connexins are dispensable for ZO1 localization. Disrupting this hierarchical ZO1/Connexin relationship abolishes electrical transmission and disrupts Mauthner-cell-initiated escape responses. We found that ZO1 is asymmetrically localized exclusively postsynaptically at neuronal contacts where it functions to assemble intercellular channels. Thus, forming functional neuronal gap junctions requires a postsynaptic scaffolding protein. The critical function of a scaffolding molecule reveals an unanticipated complexity of molecular and functional organization at electrical synapses.Competing Interest StatementThe authors have declared no competing interest.