This research project is an experimental study that seeks to understand how neuronal networks change or adapt due to the response of the retina to the gradual change in the ambient light level that occurs day and night, and the influence of the circadian (24-h) clock that is intrinsic to the retina. The release of the neuromodulator dopamine in the retina is controlled by the retinal clock, which increases dopamine levels sufficiently at dawn to activate the highly sensitive dopamine D4 receptors on cones. In addition, distinct non- circadian light responsive processes increase dopamine levels to a much greater extent in response to bright illumination at midday so that the less sensitive dopamine D1 receptors on dendrites of cone bipolar cells, a type of second order cell that receives synaptic input from cones, are activated. The proposed experiments will study whether the bright light-induced increase in D1 receptor activation strengthens GABA signaling from horizontal cells (another type of second order cell that receives cone input) to cone bipolar cells in the day by enhancing GABAA receptor function of cone bipolar cell dendrites. The proposed experiments will also investigate whether the retinal clock, by decreasing D4 receptor activation at night, strengthens GABA signaling from horizontal cells to cones at night in the dark by enhancing GABAA receptor function of cone synaptic terminals. Electrophysiological recording in rabbit retinal slices will be used to study the light responses and GABAA receptor activity of cone bipolar cells and GABA signaling from horizontal cells to cone bipolar cells. Also, electrophysiological recording in intact goldfish and rabbit neural retinas will be used to study the light responses and GABAA receptor activity of cones and GABA signaling from horizontal cells to cones. Neurochemical, cell/molecular, and anatomical techniques will also be employed using intact rabbit and fish retinas, studied in the day and night under constant darkness, and in the day following maintained illumination.
The circadian clock in the retina regulates the neuromodulator dopamine and the function of dopamine and GABA receptors. Because disruption of circadian clock processes in the retina may mediate photoreceptor cell degeneration, increased knowledge of circadian clock processes and pathways and dopamine and GABA receptors and chloride cotransporter activity in the adult retina will aid in the understanding of human retinal processes and dysfunction, as well as provide the basis for drug therapy for retinal disorders, such as night blindness that may involve the retinal circadian clock, and retinal ischemia that involves GABA receptors and the chloride cotransporters. In addition, because dopamine has been implicated in the neuronal death that occurs in Parkinson's disease, ischemic brain injury, Huntington's disease, multiple sclerosis, Alzheimer's disease, and HIV-associated dementia, increased knowledge of the actions of dopamine in the retina may aid in the understanding and treatment of these brain diseases. Moreover, increased knowledge of GABA receptors and chloride cotransporters may aid in the understanding and treatment of epilepsy and neural trauma that involve perturbations in chloride homeostasis and GABA receptor function.
