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.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
Project #
Application #
Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Greenwell, Thomas
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Los Angeles
Schools of Medicine
Los Angeles
United States
Zip Code
Rodriguez, Allen R; de Sevilla Müller, Luis Pérez; Brecha, Nicholas C (2014) The RNA binding protein RBPMS is a selective marker of ganglion cells in the mammalian retina. J Comp Neurol 522:1411-43
De Sevilla Müller, Luis Pérez; Liu, Janelle; Solomon, Alexander et al. (2013) Expression of voltage-gated calcium channel ?(2)?(4) subunits in the mouse and rat retina. J Comp Neurol 521:2486-501
Zhang, Qi; Vuong, Helen; Huang, Xin et al. (2013) Melanopsin-expressing retinal ganglion cell loss and behavioral analysis in the Thy1-CFP-DBA/2J mouse model of glaucoma. Sci China Life Sci 56:720-30
Guo, Chenying; Stella Jr, Salvatore L; Hirano, Arlene A et al. (2009) Plasmalemmal and vesicular gamma-aminobutyric acid transporter expression in the developing mouse retina. J Comp Neurol 512:6-26
Stella Jr, Salvatore L; Hu, Wanda D; Brecha, Nicholas C (2009) Adenosine suppresses exocytosis from cone terminals of the salamander retina. Neuroreport 20:923-9
Stella Jr, Salvatore L; Li, Stefanie; Sabatini, Andrea et al. (2008) Comparison of the ontogeny of the vesicular glutamate transporter 3 (VGLUT3) with VGLUT1 and VGLUT2 in the rat retina. Brain Res 1215:20-9
Raymond, Iona D; Vila, Alejandro; Huynh, Uyen-Chi N et al. (2008) Cyan fluorescent protein expression in ganglion and amacrine cells in a thy1-CFP transgenic mouse retina. Mol Vis 14:1559-74
Stella Jr, Salvatore L; Hu, Wanda D; Vila, Alejandro et al. (2007) Adenosine inhibits voltage-dependent Ca2+ influx in cone photoreceptor terminals of the tiger salamander retina. J Neurosci Res 85:1126-37
Chang, Bo; Heckenlively, John R; Bayley, Philippa R et al. (2006) The nob2 mouse, a null mutation in Cacna1f: anatomical and functional abnormalities in the outer retina and their consequences on ganglion cell visual responses. Vis Neurosci 23:11-24
Casini, Giovanni; Rickman, Dennis W; Brecha, Nicholas C (2006) Expression of the gamma-aminobutyric acid (GABA) plasma membrane transporter-1 in monkey and human retina. Invest Ophthalmol Vis Sci 47:1682-90

Showing the most recent 10 out of 61 publications