Purchase this article with an account.
R. F. Miller, E. C. Gustafson, E. R. Stevens, S. J. Sullivan, M. Esguerra, B. T. Reed, C. W. Morgans; How D-Serine Regulation Controls NMDA Receptors in Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2009;50(13):1411.
Download citation file:
© ARVO (1962-2015); The Authors (2016-present)
Characterize the mechanisms which regulate D-serine and its contribution to ganglion cell excitability through modulation of the NMDA receptor coagonist sites
Salamanders and mice with different genetic deficiencies (DAAO-/-) or knockout conditions (GlyT1-/+) were studied through whole-cell recordings from retinal ganglion cells. Both the extracellular bathing environment and tissue levels of D-serine were determined using capillary electrophoresis for separation and detection. Immunostaining and histochemical methods were used to detect the presence of D-serine regulatory pathways in the retina
In the perfused retina-eyecup, the NMDARs of ganglion cells generate larger responses when exogenous D-serine is added to the bathing medium, suggesting a consistent, unsaturated state of the NMDAR coagonist sites. Three means of regulating D-serine levels are through i) its synthesis by serine racemase (SR); ii) its degradation through D-amino acid oxidase (DAAO) and iii) the uptake of D-serine through an ASCT2 type amino acid transporter. All three regulatory pathways are present in the retina. Reducing the uptake of glycine by reducing expression of the GlyT1 transporter (GlyT1-/+) or blocking it pharmacologically (NFPS) enhances or saturates NMDAR coagonist sites. Similarly, the absence of DAAO (mutant mouse:DAAO-/-) or blocking the enzyme (Na Benzoate) increases the occupancy or saturates the NMDAR coagonist sites. Conversely, blocking SR (phenazine ethosulfate), decreases the amplitude of light-evoked NMDAR currents, an effect that can be reversed by adding D-serine. In addition, studies of D-serine release favor a mechanism involving the activation of an AMPA receptor pathway present in glial cells
Extracellular levels of D-serine are dynamically regulated so that the coagonist sites of NMDARs observed in ganglion cells are incompletely saturated, allowing for dynamic modulation of these specialized receptors under different states of light and dark adaptation
This PDF is available to Subscribers Only