Gain control by sparse, ultra-slow glycinergic synapses

In the retina, ON starburst amacrine cells (SACs) play a crucial role in the direction-selective circuit, but the sources of inhibition that shape their response properties remain unclear. Previous studies demonstrate that ∼95% of their inhibitory synapses are GABAergic, yet we find that the light-evoked inhibitory currents measured in SACs are predominantly glycinergic. Glycinergic inhibition is extremely slow, relying on non-canonical glycine receptors containing α4 subunits, and is driven by both the ON and OFF retinal pathways. These attributes enable glycine inputs to summate and effectively control the output gain of SACs, expanding the range over which they compute direction. Serial electron microscopic reconstructions reveal three specific types of ON and OFF narrow-field amacrine cells as the presumptive sources of glycinergic inhibition. Together, these results establish an unexpected role for specific glycinergic amacrine cells in the retinal computation of stimulus direction by SACs. [Display omitted] •ON starburst amacrine cells (SACs) receive a powerful ON/OFF glycinergic inhibition•Glycinergic input to SACs is sparse and ultra-slow and relies on α4-containing GlyRs•Glycinergic pathways control SAC output gain and direction selectivity•SBEM reveals specific types of narrow-field amacrine cells connect to SACs The role of glycine inhibition in controlling starburst function has often been overlooked, owing to the weak anatomical representation of glycinergic synapses in the circuit. Jain et al. demonstrate that the sparse population of glycinergic synapses uses specialized Glyα4 receptors to mediate a slow inhibition, which powerfully controls starburst output gain and direction selectivity.