Plasticity of auditory electrical synapses

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Abstract Electrical synapses, mediated by neuronal gap junctions (GJs), are widespread throughout the auditory pathway. However, the functional roles and properties of electrical synapses in the auditory system remain poorly understood. Our proposal aims to contribute to a better understanding of the properties of electrical synaptic transmission in the auditory system by investigating the molecular mechanisms responsible for plastic changes of electrical transmission at ‘mixed’, electrical and chemical, synaptic contacts that couple primary auditory afferents to the Mauthner (M-) cells in fish. Facilitated by their unique experimental accessibility, our previous investigations revealed that electrical (and chemical) transmission at these mixed synapses undergo activity- dependent synaptic potentiation. There is a prevailing perception that modifications of electrical transmission only result from direct modification of the properties of already existing GJ channels. This interpretation results from the narrow belief that electrical synapses represent simple clusters of intercellular channels. However, rather than fixed, GJs are quite dynamic structures at which channels turn over to maintain their strength at rates comparable to those of glutamate receptors in chemical synapses. Accordingly, our progress indicates that regulated insertion and removal of GJ channels governed by a molecular scaffold critically contributes to regulate electrical synapses. We found that the function of ZO-1, a postsynaptic scaffolding protein, is required for the presence of connexins (the channel-forming proteins). This finding represents a paradigm shift in the understanding of the molecular mechanisms underlying electrical transmission by demonstrating the hierarchy of associated intracellular scaffolding proteins over channel-forming proteins. Furthermore, while electrical transmission is generally thought to occur from single canonical oval-shaped GJ plaques, our preliminary results show that an electrical synapse operates with multiple GJs requiring the functional association with additional structures, such as nearby adherens junctions. By taking advantage of the experimental accessibility provided by these auditory mixed synapses and the zebrafish (ZF) model, we propose to expand the molecular, organizational, and functional framework of the electrical synapse, to encompass the complexity required to support plastic changes of function. Our approach provides a powerful window for the analysis of electrical transmission at which detailed molecular mechanisms will be investigated by combining in-vivo imaging of transgenic fish at which GJ proteins are tagged with fluorescent proteins, electrophysiology and detailed anatomical analysis using expansion microscopy with powerful genetic manipulations. Aim 1, is to determine the role of ZO-1 in mediating plasticity of electrical transmission. Aim 2, is to investigate the functional contribution of additional scaffold components to plastic changes of electrical transmission. Aim 3, is to expose the components and anatomical organization of an electrical synapse. In particular, the aim will explore the anatomical and functional relationship between GJs and adherens junctions, which evidence suggests promotes the insertion of new GJ channels, therefore suggesting a potential role in synaptic transmission and its plasticity. The description of novel molecular mechanisms involved in their regulation will contribute to a better understanding of the dynamics of circuits relevant to auditory dysfunction and the potential identification of novel therapeutic targets.