Visual signals are encoded and transmitted in the retina through synaptic interactions between retinal neurons. This rapid neural communication is, in turn, shaped by the influence of neuromodulators - transmitters that induce slow and sustained changes in the properties of neurons and synapses, and which are critical in adapting retinal neural networks to different stimulus conditions. Our long-term goal is to understand fundamental cellular and molecular mechanisms mediating modulation of retinal neurons and synapses, and to define the impact of modulatory events at these loci on the function of retinal circuitry. To extend and expand our studies of the mechanisms of retinal synaptic plasticity we propose the following three experimental aims that build directly upon our previous work: (I) Retinoic Acid and Modulation of Retinal Electrical Synapses and Gap Junction Hemichannels - we will use electrophysiology, biochemistry and RAR-specific antibodies to elucidate the novel mechanism by which retinoic acid modulates the gating of gap junction channels. We will also use electrophysiological experiments to reveal the potential role of retinoic acid in regulating local ephaptic synaptic feedback through its gating of gap junction hemichannels. (II) Zinc and Modulation of Retinal Glutamate Receptors - we will use single channel recording of native receptors and electrophysiological analysis and site-directed mutagenesis of a cloned retinal glutamate receptor to examine the molecular mechanisms by which the extracellular modulator zinc affects glutamatergic neurotransmission. (III) Circadian Oscillators of the Retina - we will use transgenic mice in which retinal neurons transcribing the circadian clock gene Period1 (Per1) are marked by with a dynamic GFP reporter combined with double label ICC for cell-specific markers to determine which neurons express circadian rhythms in clock genes. In addition, we will determine whether clock gene expressing neurons, including dopaminergic amacrine cells, are capable of self-sustained circadian rhythmicity. Completion of these aims will produce important insights into the mechanisms of retinal neuromodulation and provide an expanded basis for understanding the underlying mechanisms of excitotoxic cell death, photoreceptor degeneration and myopia, pathological eye conditions affected by zinc, the retinal circadian clock and its melatonin/dopamine outputs. ? ?
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