The overall goal of this program is to better understand visual image processing in the mammalian inner retina by defining and characterizing its transmitter systems, cell morphology and circuitry. The focus of these studies is on somatostatin (SRIF), a potent inhibitory transmitter localized to wide-field amacrine cells and its five G protein-coupled receptors, SSTR1-5. The proposed studies are focused on determining the presence of the SSTRs, their cellular expression patterns and relationship to SRIF-containing amacrine cell processes to address the hypothesis that SRIF has a paracrine mode of action and a modulatory influence at both the cellular and circuitry levels by acting at distinct SSTRs expressed by multiple cell populations. Investigations will also study the inhibitory actions of SRIF on intracellular Ca2+ levels in acutely isolated rodent rod bipolar cells and salamander photoreceptors, which strongly express SSTR2, to better define the modulatory action of SRIF at the cellular level.
Specific aim 1 will determine and characterize SSTR1-SSTR5 mRNA tissue and cellular distribution using RT-PCR, RNA blot hybridization and in situ hybridization immunohistochemistry using the rodent retina.
Specific aim 2 will investigate the sites of action of SRIF by defining the expression of SSTR1-SSTR5 and their relationship to SRIF fibers using immunohistochemistry in the rodent and rabbit retina.
Specific aim 3 will investigate the inhibitory action of SRIF at the cellular level using acutely isolated rodent rod bipolar cells and salamander photoreceptors with fluorometric Ca2+ imaging techniques. Studies will characterize SRIF inhibition of a K+ stimulated intracellular Ca2+ increase in these cells, and SRIF's modulation of the Go/Gi G proteins that have been implicated in the cellular action of this peptide. Finally, studies will evaluate SRIF action utilizing SRRF-1 and SRRF-2 receptor agonists. These studies will use rod bipolar cells from normal and Go- or Gi-deficient mice with a gene disruption of the alpha-o, alpha-i1, alpha-i2 or alpha-i3 subunits, and from SSTR-2-deficient mice with a gene disruption of SSTR-2. Experiments will utilize sequence-specific RNA probes, antibodies, SRIF-1 and -2 receptor agonists, and a highly specific SSTR2 antagonist to accomplish the experimental objectives of this application. Proposed studies will provide new information about the role of peptides in the modulation of retinal cells and circuitry in the inner retina, thus providing the basis for a better understanding of visual image processing in the retina. These objectives are consistent with the health-related goals of the National Eye Institute to develop more effective treatments and ultimately to prevent retinal diseases.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
3R01EY004067-21S1
Application #
6559176
Study Section
Visual Sciences C Study Section (VISC)
Program Officer
Hunter, Chyren
Project Start
1981-07-06
Project End
2004-06-30
Budget Start
2001-07-01
Budget End
2002-06-30
Support Year
21
Fiscal Year
2002
Total Cost
$52,675
Indirect Cost
Name
University of California Los Angeles
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Travis, Amanda M; Heflin, Stephanie J; Hirano, Arlene A et al. (2018) Dopamine-Dependent Sensitization of Rod Bipolar Cells by GABA Is Conveyed through Wide-Field Amacrine Cells. J Neurosci 38:723-732
Pérez de Sevilla Müller, Luis; Azar, Shaghauyegh S; de Los Santos, Janira et al. (2017) Prox1 Is a Marker for AII Amacrine Cells in the Mouse Retina. Front Neuroanat 11:39
Matynia, Anna; Nguyen, Eileen; Sun, Xiaoping et al. (2016) Peripheral Sensory Neurons Expressing Melanopsin Respond to Light. Front Neural Circuits 10:60
Wang, Yanling; Wang, Wenyao; Liu, Jessica et al. (2016) Protective Effect of ALA in Crushed Optic Nerve Cat Retinal Ganglion Cells Using a New Marker RBPMS. PLoS One 11:e0160309
Pérez de Sevilla Müller, Luis; Sargoy, Allison; Fernández-Sánchez, Laura et al. (2015) Expression and cellular localization of the voltage-gated calcium channel ?2?3 in the rodent retina. J Comp Neurol 523:1443-60
Hoon, Mrinalini; Sinha, Raunak; Okawa, Haruhisa et al. (2015) Neurotransmission plays contrasting roles in the maturation of inhibitory synapses on axons and dendrites of retinal bipolar cells. Proc Natl Acad Sci U S A 112:12840-5
Vuong, Helen E; Hardi, Claudia N; Barnes, Steven et al. (2015) Parallel Inhibition of Dopamine Amacrine Cells and Intrinsically Photosensitive Retinal Ganglion Cells in a Non-Image-Forming Visual Circuit of the Mouse Retina. J Neurosci 35:15955-70
Vuong, H E; Pérez de Sevilla Müller, L; Hardi, C N et al. (2015) Heterogeneous transgene expression in the retinas of the TH-RFP, TH-Cre, TH-BAC-Cre and DAT-Cre mouse lines. Neuroscience 307:319-37
Fernández-Sánchez, Laura; de Sevilla Müller, Luis Pérez; Brecha, Nicholas C et al. (2014) Loss of outer retinal neurons and circuitry alterations in the DBA/2J mouse. Invest Ophthalmol Vis Sci 55:6059-72
He, Meihua; Pan, Hong; Chang, Raymond Chuen-Chung et al. (2014) Activation of the Nrf2/HO-1 antioxidant pathway contributes to the protective effects of Lycium barbarum polysaccharides in the rodent retina after ischemia-reperfusion-induced damage. PLoS One 9:e84800

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