The main goal of this proposal is to continue exploration of intracellular Ca2+-dependent mechanisms that regulate voltage- and ligand-gated channels, and light-induced postsynaptic responses in retinal ganglion cells. The important role of intracellular Ca2+, and Ca2+-activated neuroregulatory processes in modulating ion channels and synaptic responses in ganglion cells, has received considerable attention in recent years. Still, it is fair to say that the mechanisms, and impact of such modulation on signal processing by ganglion cells are little understood. In neurons, including those of retina, stimulation of Ca2+ influx is sufficient to reorganize the actin cytoskeleton, which in turn influences the activity of voltage-dependent ion channels and synaptic transmission. The experimental hypothesis of this proposal is that certain Ca-dependent modulatory processes triggered by intracellular Ca2+ elevation during repetitive synaptic activity, or by release from internal stores are mediated by changes in cytoskeletal organization, i.e. its polymerization/ depolymerization. To test this hypothesis the Ca2+-dependence of the actin cytoskeleton reorganization and its effect on voltage-activated K+ and Ca2+ currents will be studied using a combination of electrophysiological (whole-cell patch clamp), and histochemical methods. Further, the contribution of actin filaments to the regulation of light-induced postsynaptic responses in ganglion cells will be investigated. Cytoskeleton-related changes in intracellular Ca2+ accumulation through different pathways (e.g. voltage-activated channels, glutamate receptor channels, or release from internal stores) will be studied by Ca2+ imaging. An exploration of the functional relationship between Ca2+ and the cytoskeleton state will contribute to our understanding the physiological roles of the actin cytoskeleton in the regulation of Ca2+-dependent neuromodulatory processes as well as Ca2+ homeostasis. These processes underlie normal retinal function and their imbalance has been linked to pathophysiology of the retina.
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