Browsing by Subject "D-serine"

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    D-serine: a study of its function and regulation in the retina.
    (2009-10) Gustafson, Eric Charles
    Activation of the NMDA-type glutamate receptor requires the simultaneous binding of both glutamate and a coagonist, either glycine or D-serine. In the inner retina, glutamate released from bipolar cells excites NMDA receptors on retinal ganglion cells and some amacrine cells. The identity of the coagonist, however, has remained unknown. Early on, the relatively high levels of glycine and its use in the retina as an inhibitory transmitter by a subset of amacrine cells led many to believe that glycine was the endogenous coagonist. The discovery that D-serine and its synthesizing enzyme, serine racemase, are both present in the retina suggested that D-serine may play a role as well. This manuscript reports results that have examined the role of D-serine in the retinas of larval tiger salamanders and in mice. These studies suggest that D-serine is the major endogenous coagonist during light-induced responses in the inner retina of both species. In addition, the regulatory mechanisms of glycine transport and of the endogenous D-serine degrading enzyme, D-amino acid oxidase, have been shown to be essential in maintaining coagonist levels below that needed to saturate the NMDA receptor. Together, the results position D-serine as a major contributor and potential modulator of excitatory neurotransmission in the retina.
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    Dynamic regulation of the NMDA receptor coagonist D-serine in the mammalian retina.
    (2011-09) Sullivan, Steven J.
    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.