This research project is an experimental study that seeks to understand the role of cation-chloride cotransporters in information processing in the retina. In the retina and elsewhere in the central nervous system, two types of chloride cotransporter, the Na-K-2Cl (NKCC) and K-Cl (KCC) cotransporters, have been identified. These chloride cotransporters regulate the intracellular chloride concentration such that KCC extrudes chloride from neurons, whereas NKCC transports chloride into cells. Thus, the neurotransmitter GABA, which opens chloride channels, hyperpolarizes neurons when the chloride equilibrium potential is more negative than the resting membrane potential due to the action of KCC. In contrast, GABA depolarizes neurons when the chloride equilibrium potential is more positive than the resting membrane potential due to the action of NKCC. Thus, depending on the type of chloride cotransporter expressed by a retinal neuron, GABA will either hyperpolarize or depolarize the cell. We will therefore determine the roles of chloride cotransporters in the retina by using a combination of electrophysiological, neurochemical, cell/molecular and anatomical techniques. The rabbit eyecup neural retina preparation will be used to study the roles of chloride cotransporters in directional selectivity and in synaptic transmission in the outer retina. Specifically, we will determine whether chloride cotransporter activity mediates the receptive field surround of bipolar cells and ganglion cells under light- adapted conditions. We will also determine the roles of the chloride cotransporters in the directionally selective light responses of starburst amacrine cells, interneurons that are pre-synaptic to ON-OFF directionally selective ganglion cells.
Increased knowledge of chloride cotransporter activity in the adult retina will aid in the understanding of human retinal function and dysfunction, as well as provide the basis for drug therapy for retinal disorders, such as retinal ischemia, that involve the chloride cotransporters. In addition, increased knowledge of chloride cotransporters may aid in the understanding and treatment of epilepsy and other diseases that involve chloride homeostasis and GABA.
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|Thoreson, Wallace B; Mangel, Stuart C (2012) Lateral interactions in the outer retina. Prog Retin Eye Res 31:407-41|
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|Dmitriev, Andrey V; Mangel, Stuart C (2006) Electrical feedback in the cone pedicle: a computational analysis. J Neurophysiol 95:1419-27|
|Gavrikov, Konstantin E; Nilson, James E; Dmitriev, Andrey V et al. (2006) Dendritic compartmentalization of chloride cotransporters underlies directional responses of starburst amacrine cells in retina. Proc Natl Acad Sci U S A 103:18793-8|
|Ribelayga, Christophe; Wang, Yu; Mangel, Stuart C (2004) A circadian clock in the fish retina regulates dopamine release via activation of melatonin receptors. J Physiol 554:467-82|
|Dmitriev, Andrey V; Mangel, Stuart C (2004) Retinal pH reflects retinal energy metabolism in the day and night. J Neurophysiol 91:2404-12|
|Gavrikov, Konstantin E; Dmitriev, Andrey V; Keyser, Kent T et al. (2003) Cation--chloride cotransporters mediate neural computation in the retina. Proc Natl Acad Sci U S A 100:16047-52|
|Ribelayga, Christophe; Mangel, Stuart C (2003) Absence of circadian clock regulation of horizontal cell gap junctional coupling reveals two dopamine systems in the goldfish retina. J Comp Neurol 467:243-53|