The long-term goal of this program is to understand visual processing in the mammalian retina by defining its cellular and circuitry organization. The focus of the proposed studies is on somatostatin (SRIF) and its Gi/o- protein coupled receptors (sst1-sst5). SRIF is localized to wide-field amacrine cells, suggesting it acts broadly on multiple retinal cell populations to influence visual information processing. Our studies show an unexpected complexity in the expression of sst in the inner retina, including a differential expression of ssts by bipolar, amacrine and ganglion cells. Preliminary findings indicate a light-evoked increase of SRIF synthesis, similar to light-evoked changes in dopamine (DA) synthesis, the expression of ssts by DA-containing amacrine and ganglion cells, and SRIF action on voltage-gated ion channels of ganglion cells. Together, these findings indicate a complex and differential action of SRIF on distinct retinal cell networks.
We aim to establish the mechanisms underlying two identified actions of SRIF: 1) interaction with the DA amacrine cell network, and 2) direct modification of retinal output via modulation of ganglion cell Ca2+ signaling and excitability. Proposed studies will test the hypothesis that SRIF, which is increased by light, exerts its actions at both the cellular and circuitry levels in the inner retina by acting at DA amacrine and ganglion cells.
Specific Aim 1 will test the hypothesis that SRIF influences DA release and light signaling pathways in the inner retina. Experiments will determine A) SRIF and DA amacrine cell connectivity, B) mechanisms underlying SRIF modulation of voltage-gated ion channels in DA amacrine cells, and C) light-evoked, diurnal and circadian influences on retinal SRIF synthesis and content.
Specific Aim 2 will evaluate the neuronal targets of SRIF and define their organization. Experiments will determine A) the type and structure of sstganglion cells, B) the bipolar and amacrine cell synaptic inputs to sst1 and sst4 ?-ganglion cells, and C) the projections of sst4 ?- ganglion cells.
Specific Aim 3 will test the idea that SRIF acts at sst4 ?-ganglion cells to modulate voltage- gated ion channels and neuronal excitability. Experiments will determine A) SRIF action and potency, B) SRIF modulation of spike properties, and C) SRIF action on voltage-gated ion currents expressed by ?-ganglion cells. Experimental studies will use biochemistry, immunohistochemistry, imaging and electrophysiology with rats, and wild type and transgenic mouse lines having fluorescent-labeled DA amacrine and ganglion cells. Proposed studies are of importance for elucidating the functional role of SRIF, a signaling molecule with broad modulatory influences in the retina, and they will provide the basis for a better understanding of light adaptive processes by the retina. These objectives are consistent with the health-related goals of the National Eye Institute for the development of therapeutic approaches for the treatment and prevention of retinal disease.

Public Health Relevance

Proposed studies will provide new information about the role of somatostatin (SRIF) in the modulation of retinal cells and circuitry in the inner retina, thus increasing our understanding of light adaptive processes and visual image formation by the retina. This is of particular importance since SRIF receptor agonists, including octreotide are being used for treatment of ocular disease, including proliferative diabetic retinopathy and cystoid macular edema. The clinical use of SRIF receptor agonists requires a thorough understanding of the effects of these drugs not only in pathophysiology, but also in normal retinal function, including visual processing, a fundamental objective of the proposed studies.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY004067-33
Application #
8523861
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
1981-07-06
Project End
2014-08-31
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
33
Fiscal Year
2013
Total Cost
$468,525
Indirect Cost
$164,288
Name
University of California Los Angeles
Department
Neurosciences
Type
Schools of Medicine
DUNS #
092530369
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
Sargoy, Allison; Sun, Xiaoping; Barnes, Steven et al. (2014) Differential calcium signaling mediated by voltage-gated calcium channels in rat retinal ganglion cells and their unmyelinated axons. PLoS One 9:e84507
Farrell, Spring R; Sargoy, Allison; Brecha, Nicholas C et al. (2014) Modulation of voltage-gated Ca2+ channels in rat retinal ganglion cells by gabapentin. Vis Neurosci 31:47-55

Showing the most recent 10 out of 82 publications