Grant: Project Grant

Complex structures called gap junctions located at neuronal membrane appositions create electrical synapses that allow for high-speed bi-directional electrical communication between neurons. Electrical synapses are composed of junction-forming connexin proteins, one of which is connexin36 (Cx36). Our research and that of others has indicated that these synapses are abundant in all major areas of the mammalian brain. It has recently become clear that such synapses play crucial roles in synchronizing activities of neuronal populations, thereby contributing to the high-frequency network activities that are an essential means of information processing by neurons. We have recently discovered that connexin45 (Cx45) may also form electrical synapses at many diverse locations and subcellular sites in the brain. Currently, however, physiological roles of electrical transmission mediated by gap junctions containing Cx45 remain almost entirely unexplored. One highly novel site at which we find Cx45 is at the initial segments of axons stemming from neuron cell bodies, specifically at axons of what are called pyramidal cells in the hippocampus, a structure essential for memory storage and retrieval. Amazingly, the presence of electrical synapses at that location was predicted from the activity of pyramidal cells and from computer modeling nearly fifteen years ago. Using anatomical approaches, manipulations of Cx45 gene expression and electrophysiological analyses, we will determine the organization of electrical synapses formed by Cx45 along neuronal axons and establish their functional contribution to the collective activity of pyramidal cells. Our results are expected to provide new understanding of how electrical synapses govern the network behavior of populations of neurons, and will be relevant to CNS disorders such as epilepsy, in which electrical synapses have been implicated and which is especially prone to occur in the hippocampus of epilepsy patients.