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This Week in The Journal

Vision in dim light is mediated by the rod photoreceptor pathway. Rods connect to rod bipolar cells, which in turn form glutamatergic synapses with AII and A17 amacrine cells. AII amacrine cells are required for transmitting information from rods to retinal ganglion cells (by way of cone bipolar cells), whereas A17 amacrines provide feedback inhibition to rod bipolar cells. Both AII and A17 amacrine cells express NMDA receptors (NMDARs), but these are not thought to contribute to EPSCs in the cells. Veruki et al. therefore asked what the function of these NMDARs might be. They first confirmed that EPSCs in amacrine cells in rat retinal slices were generated solely by nonNMDA glutamate receptors. Nevertheless, NMDA elicited inward currents and calcium elevation in both amacrine cell types. Furthermore, NMDA increased the frequency of IPSCs in rod bipolar cells, most likely by triggering GABA release from A17 amacrines. Notably, selectively blocking NMDARs containing GluN2B subunits eliminated NMDA-evoked responses only in AII amacrine cells, whereas selectively blocking NMDARs containing GluN2A subunits eliminated responses only in A17 amacrines. The selective expression of these subunits in AII and A17 amacrine cells was further supported by immunolabeling. Moreover,consistentwithpreviousworksuggesting that NMDARs regulate electrical coupling between AII amacrine cells and ON cone bipolar cells, GluN2B colocalized with gap-junction proteins in AII amacrines. Importantly, NMDAR antagonists reduced baseline fluctuations in membrane currents in both AII and A17 amacrine cells, suggesting that these receptors are tonically activated by ambient glutamate. Furthermore, inhibiting glutamate uptake, which is expected to increase extracellular glutamate levels, increased high-frequency current fluctuations in both amacrine cell types, and this effect was blocked by NMDAR antagonists. These results suggest that increases in ambient glutamate levels influence transmission in the rod pathway by acting on distinct extrasynaptic NMDAR types in AII and A17 amacrine cells. Activation of GluN2B-containing NMDARs in AII amacrine cells might regulate coupling between these cells and cone bipolar cells, and thus influence the transmission of light information to retinal ganglion cells. Activation of GluN2A-containing NMDARs in A17 amacrines, in contrast, likely inhibits further glutamate release from rod bipolar cells. Future work should investigate how these receptors influence visual processing at the network level.