Multireceptor GABAergic regulation of synaptic communication in amphibian retina

1. The synaptic output of retinal bipolar cells was monitored by recording light-evoked EPSCs in ganglion cells. 2. Application of (RS)-2-amino-3-(3-hydroxy-5-tert-butyl-4-isoxazolyl (ATPA ), a selective agonist at kainate receptors, depolarized amacrine cells and reduced the light-evoked excitatory current (L-EPSC) in ganglion cells. AT PA had only a slight effect on the light responses of bipolar cells. Theref ore, ATPA suppresses bipolar cell synaptic output to ganglion cells. 3. ATPA reduced the transient L-EPSC, but had comparatively little effect o n sustained L-EPSC, of ganglion cells. The transient. ON L-EPSC was more su ppressed than the transient OFF L-EPSC. Thus, ATPA preferentially suppresse d transient output from bipolar cells. 4. GABA receptor antagonists blocked the effect of ATPA. This indicates tha t ATPA stimulated an endogenous inhibitory feedback pathway that suppressed bipolar cell output. 5. CGP55845 and CGP35348 reduced the ATPA-induced suppression of L-EPSCs in ganglion cells, signifying that part of the feedback pathway is mediated b y metabotropic GABA receptors. 6. (1,2,5,6-Tetrahydropyridine-4-yl)-methylphosphinic acid (TPMPA) and picr otoxin, GABA(C) receptor antagonists, reduced the ATPA effect. Picrotoxin w as more effective than ATPA. However, picrotoxin blocked only a part of thi s GABA(C) effect, while imidazole-4-acetic acid (I4AA) blocked another segm ent of the effect. This indicates that two pharmacologically distinct. GABA (C) receptors mediate feedback to bipolar cells. 7. SR95531 produced a very small suppression of the ATPA effect. Thus, GABA (A) receptors provide a negligible component to this feedback pathway. 8. The experiments indicate that endogenous GABAergic feedback to bipolar c ells suppresses their output, and that this feedback is mediated by at leas t three types of GABA receptor, both metabotropic and ionotropic. 9. In conjunction with previous studies, the results indicate that feedback inhibition is the predominant factor regulating transient signalling in ga nglion cells, while feedforward inhibition is the primary regulator of toni c ganglion cell signals.