Dynamic regulation of the NMDA receptor coagonist D-serine in the mammalian retina.
2011-09
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Dynamic regulation of the NMDA receptor coagonist D-serine in the mammalian retina.
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2011-09
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The N-methyl D-aspartate (NMDA) receptor coagonist D-serine is important in a number of different processes in the central nervous system, ranging from synaptic plasticity to disease states, including schizophrenia. In the retina, light-evoked responses of retinal ganglion cells are shaped in part by NMDA receptors which require a coagonist for activation. There is debate over whether glycine or D-serine is the endogenous coagonist of retinal ganglion NMDA receptors. I used a mutant mouse lacking functional serine racemase (SRKO), the only known D-serine synthesizing enzyme in mammals, to show that retinal ganglion cells depend on D-serine for NMDAR activation (chapter 1).
Most changes in NMDA receptor currents during synaptic activity have been attributed to glutamate fluctuations against a steady background of coagonist, excluding the possibility of dynamic coagonist release. The retina is a particularly useful system to determine if coagonist release occurs in the nervous system, because it can be naturally stimulated with light. By saturating the glutamate binding site of NMDA receptors, I was able to measure coagonist release during light-evoked responses. Coagonist release was detected in retinal ganglion cell light responses and depended on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic AMPA receptors. Coagonist release was significantly lower in SRKO mice (chapter 2). By directly measuring extracellular D-serine using capillary electrophoresis, I demonstrated that D-serine can be released from the intact mouse retina through an AMPA receptor dependent mechanism (chapter 3). The collective works put forth in this thesis imply that activity-dependent modulation of D-serine availability may add an extra dimension to NMDA receptor coincidence detection in the central nervous system.
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University of Minnesota Ph.D. dissertation. September 2011. Major: Neuroscience. Advisor: Robert F. Miller. 1 computer file (PDF); vi, 82 pages.
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Sullivan, Steven J.. (2011). Dynamic regulation of the NMDA receptor coagonist D-serine in the mammalian retina.. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/117476.
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