Grant: Project Grant

Neurotransmitters are used by nerve cells in the brain to communicate with each other at chemical synapses. However, over the past 20 years, discoveries by us and others have shown that neuronal communication mediated by electrical synapses is also prevalent in the mammalian brain. Neural integration at electrical synapses is critical for information processing related to cognitive, sensory and motor functions. Such synapses are formed by structures called gap junctions located at close appositions between neurons, and are composed of the gap junction-forming protein connexin36. Our work has shown that these structures have many protein components supporting their assembly and neurotransmission capabilities. Understanding the functions of those components is essential for deciphering how electrical synapses operate. Our past and more recent discoveries of major protein constituents of electrical synapses (ZO-1, MUPP1, AF6, cingulin, N-cadherin, nectin-1, alpha-catenins and beta-catenin, SynGAP1, LNX1/2), has led us to explore novel biochemical mechanisms (i.e., cAMP/Epac/Rap1 signalling) that may govern the structure and deployment of these synapses in neuronal circuits. Further, we aim to investigate the role of this signalling in regulating dynamic changes in the fidelity and strength of electrical synaptic transmission, which were recently recognized as key features of electrical synapses. This signalling has links to brain disorders, as indicated by our finding SynGAP1 at electrical synapses. This protein is essential at chemical synapses and may be equally important at electrical synapses. Mutations in the gene coding for this protein were found to cause intellectual disability, autism and epilepsy in people. We expect that our work will reveal entirely new concepts on cellular mechanisms that govern the activities of electrical synapses and how malfunction of those mechanisms could contribute to neurological disorders.