GABA Inhibition Controls the Threshold Sensitivity of Retinal Ganglion Cells Independent of Dopaminergic Circuitry

Abstract

Purpose: Dark-adapted retinal ganglion cells (RGCs) in the mouse retina can be differentiated based on their extensive range of threshold sensitivities covering 3 log units (Volgyi et al., 2004). We previously showed that blockade of GABA circuits shifted the thresholds of RGCs suggesting that inhibition controls their sensitivity. Here we used selective GABA receptor blockers to determine the location of the inhibitory circuits and examined whether they interact with dopaminergic pathways that also affect neuronal sensitivity (Li & Dowling, 2000; Hermann et al., 2011).

Methods: The light-evoked responses of RGCs in C57BL mouse retinas were obtained using tungsten microelectrode or multielectrode array recordings. Intensity-response functions and threshold sensitivities were then computed from responses to varying intensity, full-field light stimulation.

Results: Application of the nonselective GABA blocker PTX (100 μM) produced a leftward shift of most RGC I-R functions indicating an increase in sensitivity. Application of the selective GABA_A receptor blocker SR-95531 (20 μM) had minimal effect on the thresholds of RGCs. However, application of the selective GABA_C receptor blocker TPMPA (100 μM) increased the sensitivity of most RGCs by 1-3 log units, comparable to the effects of PTX alone. Application of the dopamine D2 receptor blocker eticlopride (25 μM) decreased the thresholds of most RGCs by 0.25 -1.00 log unit, but subsequent application of PTX still produced an increase in sensitivity. Consistent with this finding, the increase in sensitivity of RGCs produced by PTX was never reversed by subsequent application of eticlopride. Application of the D1 receptor blocker SCH-23390 (10 μM) decreased the thresholds of most RGCs by 0.25-0.50 log units, but subsequent application of PTX increased the thresholds of RGCs. Likewise, the increase in sensitivity produced by PTX was not reversed by subsequent application of SCH-23390.

Conclusions: Our results indicate that inhibition derived mainly by activation of GABA_C receptors controls the threshold sensitivity of RGCs. Dopaminergic circuits also control the sensitivity of RGCs, but this action is relatively small compared to that of the GABAergic inhibition. Moreover, the GABAergic control of RGC sensitivity appears independent of that provided by dopaminergic circuitry.

Keywords: 531 ganglion cells • 693 retinal connections, networks, circuitry • 691 retina: proximal (bipolar, amacrine, and ganglion cells)