Intrinsic oscillatory activity arising within the electrically coupled AII amacrine–ON cone bipolar cell network is driven by voltage‐gated Na<sup>+</sup> channels
Bibliographic record
Abstract
Key points In mouse models for retinal degeneration, photoreceptor death leads to membrane oscillation in the remnant AII amacrine–ON cone bipolar cell network through an unknown mechanism. We found such oscillations require voltage‐gated Na + channels and gap junctions but not hyperpolarization‐activated currents ( I h ). Na + channels are expressed predominantly in AII amacrine cells and I h in ON cone bipolar cells, and appear to interact via gap junctions to shape oscillations. Similar intrinsic oscillations arose in the wild‐type (wt) AII amacrine–ON cone bipolar cell network when photoreceptor inputs to bipolar cells were pharmacologically occluded. Computational modelling captures experimental findings when a low level of cellular heterogeneity is introduced in the coupled network. These unique insights into the cellular mechanisms underlying spontaneous activity in the degenerating retina might aid in designing the most effective strategies to restore vision using retinal prosthesis. Abstract In the rd1 mouse model for retinal degeneration, the loss of photoreceptors results in oscillatory activity (∼10–20 Hz) within the remnant electrically coupled network of retinal ON cone bipolar and AII amacrine cells. We tested the role of hyperpolarization‐activated currents ( I h ), voltage‐gated Na + channels and gap junctions in mediating such oscillatory activity. Blocking I h (1 m m Cs + ) hyperpolarized the network and augmented activity, while antagonizing voltage‐dependent Na + channels (1 μ m TTX) abolished oscillatory activity in the AII amacrine–ON cone bipolar cell network. Voltage‐gated Na + channels were only observed in AII amacrine cells, implicating these cells as major drivers of activity. Pharmacologically uncoupling the network (200 μ m meclofenamic acid (MFA)) blocked oscillations in all cells indicating that Na + channels exert their influence over multiple cell types within the network. In wt retina, occluding photoreceptor inputs to bipolar cells (10 μ m NBQX and 50 μ m l ‐AP4) resulted in a mild (∼10 mV) hyperpolarization and the induction of oscillatory activity within the AII amacrine–ON cone bipolar cell network. These oscillations had similar properties to those observed in rd1 retina, suggesting that no major degeneration‐induced network rewiring is required to trigger spontaneous oscillations. Finally, we constructed a simplified computational model that exhibited Na + channel‐dependent network oscillations. In this model, mild heterogeneities in channel densities between individual neurons reproduced our experimental findings. These results indicate that TTX‐sensitive Na + channels in AII amacrine cells trigger degeneration‐induced network oscillations, which provide a persistent synaptic drive to downstream remnant neurons, thus appearing to replace photoreceptors as the principal drivers of retinal activity.
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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 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
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".