This research project is an experimental study that seeks to understand the role of cation-chloride co-transporters in information processing in the mammalian retina. In the retina and elsewhere in the central nervous system, two types of chloride co-transporters, the Na-K-Cl and K-Cl co-transporters, have been identified. These chloride co-transporters regulate the intracellular chloride concentration such that the K-Cl co-transporter extrudes chloride from neurons, whereas the Na-K-Cl co-transporter transports chloride into cells. Thus, the neurotransmitter GABA hyperpolarizes neurons when the chloride equilibrium potential is less than the resting membrane potential due to the action of the K-Cl co-transporter. In contrast, GABA depolarizes neurons when the chloride equilibrium potential is greater than the resting membrane potential due to the action of the Na-K-Cl co-transporter. Thus, depending on the type of chloride co-transporter expressed by a retinal neuron, GABA will either hyperpolarize or depolarize the cell.We will therefore determine the roles of chloride co-transporters in the retina by using a combination of electrophysiological, neurochemical and anatomical techniques. A rabbit eyecup preparation will be used to study the roles of chloride co-transporters in directional selectivity and in synaptic transmission from horizontal cells to bipolar cells. Specifically, we will determine whether an asymmetric distribution of the Na-K-Cl and K-Cl co-transporters on starburst amacrine cells mediates the null direction inhibition exhibited by rabbit ON-OFF directionally-selective ganglion cells. We will also determine whether horizontal cells contribute to the receptive field surround of ON-center bipolar cells (and ON-center ganglion cells) in part by a direct, GABA-mediated synaptic connection that is Na-K-Cl co-transporter-dependent and sign conserving. Finally, we will determine whether and how the development of chloride co-transporter function affects these retinal phenomena.Increased knowledge of chloride co-transporter function in the adult and developing retina will aid in the understanding of human retinal processes and dysfunction, as well as provide the basis for drug therapy for retinal disorders.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY014235-02
Application #
6650240
Study Section
Special Emphasis Panel (ZRG1-SSS-P (01))
Program Officer
Hunter, Chyren
Project Start
2002-09-01
Project End
2007-07-31
Budget Start
2003-08-01
Budget End
2004-07-31
Support Year
2
Fiscal Year
2003
Total Cost
$290,000
Indirect Cost
Name
University of Alabama Birmingham
Department
Neurosciences
Type
Schools of Medicine
DUNS #
063690705
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Chaffiol, Antoine; Ishii, Masaaki; Cao, Yu et al. (2017) Dopamine Regulation of GABAA Receptors Contributes to Light/Dark Modulation of the ON-Cone Bipolar Cell Receptive Field Surround in the Retina. Curr Biol 27:2600-2609.e4
Thoreson, Wallace B; Mangel, Stuart C (2012) Lateral interactions in the outer retina. Prog Retin Eye Res 31:407-41
Dmitriev, Andrey V; Gavrikov, Konstantin E; Mangel, Stuart C (2012) GABA-mediated spatial and temporal asymmetries that contribute to the directionally selective light responses of starburst amacrine cells in retina. J Physiol 590:1699-720
Dmitriev, Andrey V; Dmitrieva, Nina A; Keyser, Kent T et al. (2007) Multiple functions of cation-chloride cotransporters in the fish retina. Vis Neurosci 24:635-45
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