Dynamic regulation of D-serine release in the vertebrate retina.

KEY POINTS: Activation of NMDA receptors (NMDARs) is essential for encoding visual stimuli into signals for the brain, although their over-activation can cause cell death. The recruitment of NMDARs is important for encoding light intensity in retinal ganglion cells. D-serine binding is essential for proper activation of NMDARs, although its role in signal processing and the mechanisms that underlie its availability are not well understood. In these light-evoked experiments, the addition of exogenous D-serine had a large effect on low contrast and low intensity NMDAR responses that decreased as the intensity was increased. The degradation of endogenous D-serine decreased the responses more at higher intensities. The results provide compelling evidence favouring a new interpretation of NMDAR recruitment in which light-evoked D-serine release serves an important regulatory control over the recruitment of NMDARs. ABSTRACT: The present study aimed to investigate the functional properties of NMDA receptor coagonist release and to specifically evaluate whether light-evoked release mechanisms contribute to the availability of the coagonist D-serine. Two different methods were involved in our approach: (i) whole-cell recordings from identified retinal ganglion cells in the tiger salamander were used to study light adaptation with positive and negative contrast stimuli over a range of ± 1 log unit against a steady background illumination and (ii) the mechanisms for intensity encoding to a range of light intensities covering 6 log10 units were investigated. This latter study employed extracellular recordings of the proximal negative field potential, pharmacologically manipulated to generate a pure NMDA mediated response. For the adaptation study, we examined the light-evoked responses under control conditions, followed by light stimuli presented in the presence of D-serine, followed by light stimulation in the presence of dichlorokynurenic acid to block the coagonist site of NMDA receptors. For the brightness encoding studies, we examined the action of D-serine on each intensity used and then applied the enzyme D-serine deaminase to remove significant levels of D-serine. These studies provided new insights into the mechanisms that regulate coagonist availability in the vertebrate retina. Our results strongly support the idea that light-evoked coagonist release, a major component of which is D-serine, is needed to provide the full range of coagonist availability for optimal activation of NMDA receptors.