Regulation of Retinal Gap Junctions

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 DESCRIPTION (provided by applicant): Neurons throughout the central nervous system employ both chemical and electrical synapses to form synaptically connected networks. Both forms of synapse are subject to plasticity through a variety of mechanisms, and such plasticity is a fundamental substrate for circuit optimization during sensory signal processing, behavior, and learning. Within the retina, electrical synapses, formed by gap junctions, contribute to the signal processing functions of most types of neurons. Electrical synaptic plasticity is a hallmark feature of visual adaptation, having profound effects on the sensitivity and receptive field properties of many neurons and influencing the path of signal flow in the mammalian rod pathway. The long-term objectives of this study are to identify the mechanisms that regulate electrical synapses in the retina and to determine which modes of regulation are most important for the adaptive processes observed in different electrically coupled neural circuits. Our earlier work has shown that signaling mechanisms that change the phosphorylation state of connexin 36 (Cx36) gap junctions can change the degree of coupling by more than an order of magnitude and do so dynamically with light adaptation. It is apparent that the mechanisms that control different electrically coupled neural networks vary, but certain themes recur throughout the central nervous system. An important role for calcium signaling via CaM Kinase phosphorylation of Cx36 is one such theme. In this project, we will examine the molecular mechanisms that mediate calcium signaling at electrical synapses. We will examine how calcium signals are delivered to the gap junctions via NMDA-type glutamate receptors and examine the role played by calmodulin binding to the connexin. We will examine the prevalence of calcium signaling at electrical synapses in the retina with a genetically encoded calcium sensor. Finally, we will investigate how molecular scaffolds form complexes that integrate different regulatory signals at electrical synapses. The results of this study will be useful to design targeted interventions to manipulate gap junctional coupling. Such interventions could be useful in incidents of retinal ischemia or similar events in other parts of the central nervous system in which neuronal gap junctional coupling exacerbates injury.