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.
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.
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