Grant: Project Grant

Numerous neurotransmitters are used by nerve cells in the brain to communicate with each other at chemical synapses. However, over the past 15 years, surprising discoveries by us and others have shown that another mode of neuronal communication mediated by electrical synapses is also prevalent in the mammalian central nervous system. These synapses are critical for information processing related to cognitive, sensory and motor functions of the brain. Such synapses are formed by structures called gap junctions that are located at close appositions between neurons, and are composed of the gap junction-forming protein connexin36 as well as a growing list of accessory proteins. Our work shows that these structures are complex, with many protein components supporting their assembly, maintenance and neurotransmission functions. Identification of those components and their functions is essential for understanding the normal operation of electrical synapses and how their malfunction could contribute to brain disorders. With our past and more recent discoveries of some of their key protein components (ZO-1, MUPP1, AF6, cingulin, N-cadherin, nectin-1, alpha-catenins and beta-catenin, SynGAP1), we aim to determine how these proteins are organized and regulate electrical synapses. Our finding of the protein SynGAP1 at these synapses is particularly intriguing, because it is already known to be important for regulating communication at chemical synapses and may be equally important at electrical synapses. Further, mutations in the gene coding for this protein were recently found to cause significant 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, which will ultimately be important for considerations of how these synapses could potentially malfunction and contribute to neurological disorders.