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T. L. Kalbaugh, J. S. Diamond; Synaptically Released Glycine Influences NMDA Receptor Activation on Retinal Ganglion Cells. Invest. Ophthalmol. Vis. Sci. 2007;48(13):4595.
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© ARVO (1962-2015); The Authors (2016-present)
Synaptic excitation of retinal ganglion cells (RGCs) is mediated by AMPA and NMDA receptors (AMPARs and NMDARs). NMDAR activation requires two ligands, glutamate and either glycine or D-serine. Glutamate is released onto RGC dendrites by ON and OFF cone bipolar cells (BCs), but the source and identity of the second ligand remain unclear. Here we examine the roles of glycine and D-serine in RGC NMDAR activation and how synaptic glycine release influences the contributions of different NMDAR subtypes.
Whole-cell voltage-clamp recordings were made from rat RGCs in acute retinal slices. Synaptic currents (EPSCs) were elicited by pharmacologically activating ON or OFF BCs with puff applications of CPPG or kainate, respectively, in the outer plexiform layer. Responsivity of individual RGCs to CPPG ("ON EPSCs") and kainate ("OFF EPSCs") correlated with responses to light stimulation.
ON and OFF EPSCs were mostly blocked by the NMDAR antagonist CPP, but ON NMDAR EPSCs also were reduced significantly by the AMPAR antagonist NBQX, which appeared to diminish release from cone BCs by eliminating input from electrically-coupled AIIs. In RGCs, saturating NMDARs with bath-applied D-serine enhanced ON EPSCs only in the presence of NBQX and had no effect on OFF EPSCs. Saturating NMDARs with bath-applied NMDA increased the holding current in RGCs and reduced, but did not eliminate, ON EPSCs. In saturating NMDA, neither the holding current nor the EPSC was affected when D-serine was degraded with D-amino acid oxidase. ON EPSCs were blocked more strongly than OFF EPSCs by the NR2B-specific antagonist Ro25-6981. NBQX decreased the relative contribution of non-NR2B receptors by reducing synaptically released glycine.
These results suggest that the NMDAR "glycine site" is not saturated by ambient ligand and that an NBQX-sensitive cell in the ON pathway influences the occupancy of the site. Ambient D-serine does not contribute to synaptic NMDAR activation. Activation of the rod pathway appears to increase occupancy of the glycine site. Distinct NMDAR subtypes respond to the stimulation of ON and OFF pathways, and the fractional contribution of NR2B-containing NMDARs appears influenced by the amount of synaptically released glycine.
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