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One general categorization of retinal ganglion cells is to segregate them into tonically or phasically responding neurons, each conveying discrete aspects of the visual scene. Although best identified in the output signals of the retina, this distinction is initiated at the first synapse: between photoreceptors and the dendrites of bipolar cells. In this study we found that the output synapses of bipolar cells also contribute to separate these pathways. Both transient and sustained ganglion cells can produce maintained spike activity, but bipolar cell glutamate release exhibits a divergence that corresponds to the response characteristics of the ganglion cells. Comparing light intensity coding in the sustained and transient ON pathways revealed that they shared the intensity spectrum. The transient pathway had greater sensitivity but smaller dynamic range, and switched from intensity coding to event detection at light levels where sustained pathway sensitivity began to rise. The distinctive properties of the sustained pathway depended upon inhibition and shifted toward those of the transient pathway in the absence of inhibition. The transient system was comparatively unaffected by the loss of inhibition and this was due to the concomitant activation of perisynaptic NMDA receptors. Overall, the properties of bipolar cell dendritic and axon terminals both contribute to the formation of key aspects of the sustained/transient dichotomy normally associated with ganglion cells.

Glycine is the lone fast neurotransmitter for which a metabotropic pathway has not been identified. In retina, we found a strychnine-insensitive glycine response in bipolar and ganglion cells. This glycine response reduced high voltage-activated calcium current. It was G-protein mediated and protein kinase A dependent. The EC(50) of the metabotropic glycine response is 3 mum, an order of magnitude lower than the ionotropic glycine receptor in the same retina. The bipolar cell glutamatergic input to ganglion cells was suppressed by metabotropic glycine action. The synaptic output of about two-thirds of bipolar cells and calcium current in two-thirds of ganglion cells are sensitive to the action of glycine at metabotropic receptors, suggesting this signal regulates specific synaptic pathways in proximal retina. This study resolves the curious absence of a metabotropic glycine pathway in the nervous system and reveals that the major fast inhibitory neurotransmitters, GABA and glycine, both activate G-protein-coupled pathways as well.

Retinal rod photoreceptors are depolarized in darkness to approximately -40 mV, a state in which they maintain sustained glutamate release despite low levels of calcium channel activation. Blocking voltage-gated calcium channels or ryanodine receptors (RyRs) at the rod presynaptic terminal suppressed synaptic communication to bipolar cells. Spontaneous synaptic events were also inhibited when either of these pathways was blocked. This indicates that both calcium influx and calcium release from internal stores are required for the normal release of transmitter of the rod. RyR-independent release can be evoked by depolarization of a rod to a supraphysiological potential (-20 mV) that activates a large fraction of voltage-gated channels. However, this calcium channel-mediated release depletes rapidly if RyRs are blocked, indicating that RyRs support prolonged glutamate release. Thus, the rod synapse couples a small transmembrane calcium influx with a RyR-dependent amplification mechanism to support continuous vesicle release.

1. We performed current-clamp and voltage-clamp experiments in the amphibian retina to examine the effects of 1-amino-1,3-cyclopentanedicarboxylic acid (1S,3R ACPD), which is a selective agonist for the family of metabotropic glutamate receptors. 2. 1S,3R ACPD was found to selectively block the light responses of ON bipolar cells. It did not suppress the responses of horizontal cells of OFF bipolar cells. It blocked ON but not OFF responses of third-order retinal neurons. 3. 1S,3R ACPD mimicked the effect of the photoreceptor transmitter at the ON bipolar synapse. It reduced an inward current by a decrease in conductance. 4. The action of 1S,3R ACPD was very similar to that of 2-amino-4-phosphonobutyrate (APB) both in terms of effects on the ON bipolar cell potential and conductance and in terms of the retinal network. This suggests that the APB receptor is a predominant synaptic metabotropic glutamate receptor in the retina. 5. The rank-order potency at the retinal APB receptor is APB > 1S,3R ACPD > ibotenate. Quisqualate appears to be inactive at this receptor. The pharmacology of the retinal APB receptor matches that of the cloned mGluR4 and mGluR6 metabotropic glutamate receptors. On the basis of the in situ localization of mGluR6 to the inner nuclear layer of the retina, the retinal APB receptor may be this cloned receptor protein. 6. The effects of the three other ACPD stereo isomers were examined. 1S,3S ACPD was a weak agonist at the APB receptor. 1R,3R ACPD was a potent agonist in the inner retina, but inactive in the outer retina. This fits the profile of N-methyl-D-aspartate agonists. 1R,3S ACPD was inactive.