Calcium channels in rat horizontal cells regulate feedback inhibition of photoreceptors through an unconventional GABA‐ and pH‐sensitive mechanism
Bibliographic record
Abstract
Key points Inhibitory feedback from horizontal cells to photoreceptors regulates synaptic gain and contributes to centre–surround receptive field formation via mechanisms that are not fully understood. We show that horizontal cell calcium channels and ionotropic GABA receptors mediate the inhibitory feedback, and that the results of their actions are blocked by strong pH buffering with Hepes. GABA appears to act not upon the photoreceptor but instead upon the horizontal cell itself. The horizontal cell GABA receptors are permeable to chloride and bicarbonate, meaning their activation can produce changes in synaptic cleft pH. These results suggest that activation of calcium channels in a depolarized horizontal cell releases GABA, which acts in an autaptic manner to increase bicarbonate permeability. The resulting influx of bicarbonate contributes to acidification of the synaptic cleft, inhibiting photoreceptor calcium channels, the hallmark of inhibitory feedback at this synapse. Abstract Horizontal cells send inhibitory feedback to photoreceptors, helping form antagonistic receptive fields in the retina, but the neurotransmitter and the mechanisms underlying this signalling are not known. Since the proteins responsible for conventional Ca2+‐dependent release of GABAergic synaptic vesicles are present in mammalian horizontal cells, we investigated this conventional mechanism as the means by which horizontal cells inhibit photoreceptors. Using Ca2+ imaging in rat retinal slices, we confirm that horizontal cell depolarization with kainate inhibits and horizontal cell hyperpolarization with NBQX disinhibits the Ca2+ signals produced by pH‐sensitive activation of voltage‐gated calcium channels (Ca channels) in photoreceptors. We show that while 100 μm Co2+ reduces photoreceptor Ca2+ signals, it disinhibits them at 10 μm, an effect reminiscent of earlier studies where low [Co2+] eliminated feedback. The low [Co2+] disinhibition is pH sensitive. We localized L‐, N‐ and P/Q‐type Ca channels in rat horizontal cells, and showed that both the N‐type Ca channel blocker ω‐conotoxin GVIA and the P/Q‐type Ca channel blocker ω‐agatoxin IVA increased Ca2+ signals in photoreceptors in a pH‐sensitive manner. Pronounced actions of GABAergic agents on feedback signals to photoreceptors were observed, and are pH sensitive, but are inconsistent with direct inhibition by GABA of photoreceptor [Ca2+]. Patch‐clamp studies revealed that GABA activates a conductance having high bicarbonate permeability in isolated horizontal cells, suggesting that the commonality of pH sensitivity throughout the results could arise from a GABA autofeedback action in horizontal cells. This could change cleft pH with concomitant inhibitory influences on photoreceptor Ca channels.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".