Art - Cook (P)

Spatial resolution and gain control are important sensory-system functions that frequently involve lateral inhibition, which can increase spatial tuning of a neuron by effectively reducing the area of its receptive-field center. In the vertebrate retina, lateral inhibition can modulate the direct pathway for light-evoked signals (photoreceptors to bipolar cells to ganglion cells) both via horizontal cells in the outer retina, where photoreceptors synapse onto bipolar cells, and via amacrine cells in the inner retina, where bipolar cells synapse onto ganglion cells. One function of horizontal cells is the modulation of synaptic gain between photoreceptors and bipolar cells1. Because horizontal cells have large receptive fields, this causes the classic sustained ‘center–surround’ antagonistic receptive-field organization of bipolar cells1–4. Many ganglion cells have a similar receptivefield organization5,6, which is thought to be mainly due to the lateral inhibition in the outer retina. This view is supported by the finding that hyperpolarizing current injection into horizontal cells, which mimics their response to light, elicits a ‘surround-like’ response in ganglion cells7,8. Inhibitory interactions via amacrine cells in the inner retina typically mediate more complex functions, such as directional selectivity and responses specifically related to changing or moving light stimuli3,9–16. Although an inner retinal contribution to steady surround responses has been suggested16,17, the extent to which this affects the size of the receptive-field center (spatial tuning) of ganglion cells has not been studied. Here we show in the tiger salamander retina that much of the sustained surround antagonism in on-center ganglion cells, particularly those with small receptive-field centers, is due to lateral inhibition in the inner retina. This inhibition is mediated by GABAergic amacrine cells, and the lateral spread of this signal through amacrine cell processes requires voltage-gated sodium currents. The functional significance of this lateral inhibition at the second synaptic level is to significantly and selectively sharpen the spatial tuning of ganglion cells. Results Because many amacrine cells fire action potentials, whereas outer retinal neurons do not, we reasoned that if there were an inner retinal contribution to sustained surround antagonism, it might be mediated by action potentials. We therefore sought to determine whether a component of the sustained surround antagonism in ganglion cells could be blocked by tetrodotoxin (TTX), which blocks voltage-dependent sodium channels. One consequence of surround antagonism is found in a cell’s spatial tuning (that is, preference for stimuli of a certain size). Increasing the size of a spot stimulus centered on the receptive field increases the response amplitude up to a certain optimal spot size, beyond which further increases in spot size decrease response amplitude. In an on-center ganglion cell (Fig. 1a), a 400-μm spot produced a large, sustained depolarization and a maintained train of action potentials, whereas a 2600-μm spot produced a smaller sustained response that generated only a single action potential at light onset. In the presence of TTX, however, enlarging the spot diameter from 400 to 2600 μm did not decrease the sustained depolarization; this effect was reversed by removing the TTX. This cell responded best to a 400-μm diameter stimulus. In most on-center ganglion cells that we recorded, the optimal spot diameter without TTX was about 400 μm (Fig. 1b). Although TTX had little effect on responses to spots that were smaller than the optimal stimulus diameter, it significantly increased the responses to larger stimuli, and thus reduced these cells’ preference for smaller spots. We also encountered a few oncenter ganglion cells in which the optimum spot diameter was as small as 100 μm or as large as 800 μm; the effects of TTX on these cells will be described later. To verify that the effect of TTX on the receptive-field profile was a network effect and not due to blocking voltage-dependent conductances in the recorded ganglion cell, we did control experiments with electrodes containing QX-314, an intracellular blocker of voltage-dependent sodium currents19. QX-314 blocked Lateral inhibition in the inner retina is important for spatial tuning of ganglion cells