Selective Glycine Receptor α2 Subunit Control of Crossover Inhibition between the On and Off Retinal Pathways

In the retina, the receptive fields (RFs) of almost all ganglion cells (GCs) are comprised of an excitatory center and a suppressive surround. The RF center arises from local excitatory bipolar cell ( BC) inputs and the surround from lateral inhibitory inputs. Selective antagonists have been used to define the roles of GABA(A) and GABA(C) receptor-mediated input in RF organization. In contrast, the role of glycine receptor ( GlyR) subunit-specific inhibition is less clear because the only antagonist, strychnine, blocks all GlyR subunit combinations. We used mice lacking the GlyR alpha 2 (Glra2(-/-)) and GlyR alpha 3 (Glra3(-/-)) subunits, or both (Glra2/3(-/-)), to explore their roles in GC RF organization. By comparing spontaneous and visually evoked responses of WT with Glra2(-/-), Glra3(-/-) and Glra2/3(-/-) ON- and OFF-center GCs, we found that both GlyR alpha 2 and GlyR alpha 3 modulate local RF interactions. In the On pathway, both receptors enhance the excitatory center response; however, the underlying inhibitory mechanisms differ. GlyR alpha 2 participates in crossover inhibition, whereas GlyR alpha 3 mediates serial inhibition. In the Off pathway, GlyR alpha 2 plays a similar role, again using crossover inhibition and enhancing excitatory responses within the RF center. Comparisons of single and double KOs indicate that GlyR alpha 2 and GlyR alpha 3 inhibition are independent and additive, consistent with the finding that they use different inhibitory circuitry. These findings are the first to define GlyR subunit-specific control of visual function and GlyR alpha 2 subunit-specific control of crossover inhibition in the retina.