Push-pull model of the primate photopic electroretinogram: a role for hyperpolarizing neurons in shaping the b-wave.
Existing models of the primate photopic electroretinogram (ERG) attribute the light-adapted b-wave to activity of depolarizing bipolar cells (DBCs), mediated through a release of potassium that is monitored by Müller cells. However, possible ERG contributions from OFF-bipolar cells (HBCs) and horizontal cells (HzCs) have not been explored. We examined the contribution of these hyperpolarizing second-order retinal cells to the photopic ERG of monkey by applying glutamate analogs to suppress photoreceptor transmission selectively to HBC/HzCs vs. DBCs. ERGs of Macaca monkeys were recorded at the cornea before and after intravitreal injection of drugs. Photopic responses were elicited by bright 200-220 ms flashes on a steady background of 3.3 log scotopic troland to suppress rod ERG components. 2-amino-4-phosphonobutyric acid (APB), which blocks DBC light responses, abolished the photopic b-wave and indicated that DBC activity is requisite for photopic b-wave production. However, applying cis-2,3-piperidine dicarboxylic acid (PDA) and kynurenic acid (KYN), to suppress HBCs/HzCs and third-order neurons, revealed a novel ERG response that was entirely positive and was sustained for the duration of the flash. The normally phasic b-wave was subsumed into this new response. Applying n-methyl-dl-aspartate (NMA) did not replicate the PDA+KYN effect, indicating that third-order retinal cells are not involved. This suggests that HBC/HzC activity is critical for shaping the phasic b-wave. Components attributable to depolarizing vs. hyperpolarizing cells were separated by subtracting waveforms after each drug from responses immediately before. This analysis indicated that DBCs and HBC/HzCs each can produce large but opposing field potentials that nearly cancel and that normally leave only the residual phasic b-wave response in the photopic ERG. Latency of the DBC component was 5-9 ms slower than the HBC/HzC component. However, once activated, the DBC component had a steeper slope. This resembles properties known for the two types of cone synapses in lower species, in which the sign-preserving HBC/HzC synapse has faster kinetics but probably lower gain than the slower sign-inverting G-protein coupled DBC synapse. A human patient with "unilateral cone dystrophy" was found to have a positive and sustained ERG that mimicked the monkey ERG after PDA+KYN, indicating that these novel positive photopic responses can occur naturally even without drug application. These results demonstrate that hyperpolarizing second-order neurons are important for the primate photopic ERG.(ABSTRACT TRUNCATED AT 400 WORDS)
Department of Ophthalmology, University of Michigan, Ann Arbor.
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Sieving
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Murayama
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Naarendorp
D000613:Aminobutyrates / Q000494:pharmacology; D000818:Animals; D004596:Electroretinography / Q000187:drug effects; D007267:Injections; D007736:Kynurenic Acid / Q000494:pharmacology; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008954:Models, Biological; D010786:Photoreceptor Cells / Q000502:physiology*; D010875:Pipecolic Acids / Q000494:pharmacology; D012162:Retinal Degeneration / Q000503:physiopathology; D014822:Vitreous Body
D000613:Aminobutyrates; D010875:Pipecolic Acids; C029262:2,3-piperidinedicarboxylic acid; D007736:Kynurenic Acid; C012729:2-amino-4-phosphonobutyric acid