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 proposed studies is on somatostatin (SRIF) and its Gi/o-protein coupled receptors (sst1-sst5). Past studies have established that SRIF is localized to wide-field amacrine cells and that there is a differential expression of ssts in the retina. Preliminary findings indicate a light-evoked increase of SRIF synthesis, similar to light-evoked changes in dopamine (DA) synthesis, and the expression of ssts by dopamine amacrine and ganglion cells. Furthermore, SRIF influences voltage-gated ion channels of bipolar cells and photoreceptors, indicating that one action of SRIF is the modulation of presynaptic transmitter release. Together, these findings suggest that SRIF acts on multiple cell populations and that it has a broad modulatory influence on visual information processing. Proposed studies will test the hypotheses that SRIF levels in the retina are increased by light, and that SRIF exerts its effects at both the cellular and circuitry levels by acting at sst receptors expressed by dopamine-containing amacrine and ganglion cells.
Specific Aim 1 will test the hypothesis that light exposure increases SRIF levels in the retina, and SRIF influences DA release and light signaling pathways in the retina. Experiments will determine A) light-evoked, diurnal and circadian influences on retinal SRIF synthesis and content, B) SRIF amacrine cell organization and circuitry, and relationship to DA amacrine cells, and C) mechanisms underlying SRIF modulation of voltage-gated ion channels in DA amacrine cells.
Specific Aim 2 will evaluate the neuronal targets of SRIF and define their network organization. Experiments will A) characterize the cellular organization of sst1 and sst4 ganglion cells, and B) determine their bipolar and amacrine cell inputs, and central projections.
Specific Aim 3 will test if SRIF acts directly at sst ganglion cells to modulate voltage-gated ion channels and neuronal excitability. Experiments will determine A) SRIF modulation of spike properties, B) SRIF and sst4 agonist effect on K+-induced [Ca]i, and C) SRIF action on voltage-gated ion channels expressed by sst ganglion cells. Experimental studies will use biochemistry, immunohistochemistry, imaging and electrophysiology with rats, and wild type and transgenic mouse lines having fluorescent DA amacrine and ganglion cells. Proposed studies are of importance for elucidating the functional role of SRIF, an important signaling molecule in the mammalian 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 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 somatostatin receptor agonists, like octreotide are being used for treatment of ocular disease, including proliferative diabetic retinopathy and cystoid macular edema. An understanding of the effects of these drugs not only in pathophysiology, but also in normal retinal function, is a fundamental objective of the proposed studies, which is consistent with the health-related goals of the National Eye Institute to develop more effective treatments and ultimately to prevent retinal diseases.
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