This research proposal is a broad investigation into the role that D-serine plays as a mediator of glial-neuronal interactions in the vertebrate retina. In this A1 revision, the scope of the grant and the budget has been significantly reduced to a subset of the previous aims. Preliminary evidence suggests that D-serine is synthesized and released by Muller cells and astrocytes and that this release is mediated by glutamate activation of AMPA receptors intrinsic to the retinal gila; D-serine serves as the endogenous coagonist with glutamate to activate NMDA receptors found in ganglion and amacrine cells of the inner retina. The research described in this application is designed to test the hypothesis that D-serine is a major factor in controlling the excitability of retinal ganglion cells and serves to modulate the retinal network operations through this action. We will also explore the possibility that D-serine has cellular actions other than that of altering NMDA receptor sensitivity. The research described in this application is designed to study the release, uptake and storage of D-serine as well as its physiological actions. The role of glycine as an NMDA coagonist will also be studied using effective blocking agents for high affinity glycine uptake systems. We will explore these mechanisms using electrophysiological recordings from single cells in the intact retina as well as studies of single dissociated Muller cells. Release of endogenous D-serine will be done using a new on-line capillary electrophoresis concept. This research plan will take advantage of the unique features of the vertebrate retina which make it an ideal target for studies of D-serine and its importance in retinal network operations and homeostasis of the retina. It is essential to understand the importance of D-serine in retinal function, as patients are now being treated for psychiatric disorders with high doses of D-serine.

National Institute of Health (NIH)
National Eye Institute (NEI)
Research Project (R01)
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Study Section
Biology and Diseases of the Posterior Eye Study Section (BDPE)
Program Officer
Hunter, Chyren
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University of Minnesota Twin Cities
Schools of Medicine
United States
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Gustafson, Eric G; Stevens, Eric S; Miller, Robert F (2015) Dynamic regulation of D-serine release in the vertebrate retina. J Physiol 593:843-56
Romero, Gabriel E; Lockridge, Amber D; Morgans, Catherine W et al. (2014) The postnatal development of D-serine in the retinas of two mouse strains, including a mutant mouse with a deficiency in D-amino acid oxidase and a serine racemase knockout mouse. ACS Chem Neurosci 5:848-54
Gustafson, Eric C; Morgans, Catherine W; Tekmen, Merve et al. (2013) Retinal NMDA receptor function and expression are altered in a mouse lacking D-amino acid oxidase. J Neurophysiol 110:2718-26
Sullivan, Steve J; Miller, Robert F (2012) AMPA receptor-dependent, light-evoked D-serine release acts on retinal ganglion cell NMDA receptors. J Neurophysiol 108:1044-51
Sullivan, Steve J; Miller, Robert F (2010) AMPA receptor mediated D-serine release from retinal glial cells. J Neurochem 115:1681-9
Stevens, Eric R; Gustafson, Eric C; Miller, Robert F (2010) Glycine transport accounts for the differential role of glycine vs. D-serine at NMDA receptor coagonist sites in the salamander retina. Eur J Neurosci 31:808-16
Stevens, Eric R; Gustafson, Eric C; Sullivan, Steven J et al. (2010) Light-evoked NMDA receptor-mediated currents are reduced by blocking D-serine synthesis in the salamander retina. Neuroreport 21:239-44
Reed, Brian T; Sullivan, Steven J; Tsai, Guochuan et al. (2009) The glycine transporter GlyT1 controls N-methyl-D-aspartic acid receptor coagonist occupancy in the mouse retina. Eur J Neurosci 30:2308-17
Perge, János A; Koch, Kristin; Miller, Robert et al. (2009) How the optic nerve allocates space, energy capacity, and information. J Neurosci 29:7917-28
Balasubramanian, Vijay; Sterling, Peter (2009) Receptive fields and functional architecture in the retina. J Physiol 587:2753-67

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