Characterization of calcium-permeable AMPA receptors in the developing retina and cerebellum
Bibliographic record
Abstract
Characterization of calcium-permeable AMPARs in the developing retina and cerebellumIn developing neurons, calcium (Ca 2+ ) influx through NMDA-selective ionotropic glutamate receptors is central to neuronal maturation.However, not all cells express NMDA receptors (NMDARs), suggesting that other Ca 2+ -permeable glutamate receptors may be important to consider.In particular, Ca 2+ -permeable AMPA receptors (CP-AMPARs) are expressed throughout the adult central nervous system, but their role in development remains poorly understood.Here, we employed a modified cobalt staining technique to assay the presence of CP-AMPARs in living neurons, in combination with electrophysiology.We identified two inhibitory retinal cells, horizontal cells (HC) and AII amacrine cells, which though devoid of NMDARs express CP-AMPARs.We found that CP-AMPARs were present at all stages of the development.Yet, right before eye-opening, they exhibited a pharmacological resistance to philanthotoxin (PhTX).This finding was unexpected since external synthetic polyamines such as PhTX are routinely used to selectively block CP-AMPARs.Interestingly, polyamine-insensitive receptors failed to express in animals reared in the dark, demonstrating that light entering the eye triggers their appearance.This occurred through a BDNF (brainderived neurotrophic factor)-dependent pathway since exogenous application of the neurotrophin rescued polyamine-resistance in dark-reared rats.Polyamineinsensitivity of CP-AMPARs is assumed to originate from the presence of the AMPAR subunit GluA2.To investigate this possibility, we performed experiments on GluA2 knock-out animals.GluA2 was found to be needed to render CP-AMPARs insensitive to PhTX in retinal HC and AII amacrine cells.We further established that adult cerebellar basket, stellate and Purkinje cells also possessed CP-AMPARs that were polyamine-resistant, because of GluA2 surface expression.Finally, we provide evidence indicating that these novel receptors are ii implicated in disease states.Together, we demonstrate for the first time that a population of AMPARs that contain GluA2 are also Ca 2+ -permeable.Their expression is driven by sensory experience centered around the GluA2 subunit.Given the absence of synaptic NMDARs, our work suggests that new mechanisms of synapse regulation may be in place during development of these synapses.iii RsumCaractrisation des rcepteurs AMPA permables au calcium dans la rtine et le cervelet en dveloppement Dans les neurones en dveloppement, l'influx de calcium (Ca 2+ ) travers les rcepteurs ionotropes au glutamate slectifs pour le NMDA est central pour la maturation neuronale.Cependant, toutes les cellules n'expriment pas des rcepteurs NMDA (NMDARs), suggrant que d'autres rcepteurs au glutamate permables au Ca 2+ soient importants considrer.En particulier, les rcepteurs AMPA permables au Ca 2+ (CP-AMPARs) sont exprims travers le systme nerveux central adulte, mais leurs rles durant le dveloppement restent mal compris.Ici, nous avons employ une technique modifie de la coloration au cobalt pour rvler la prsence des CP-AMPARs dans les neurones vivants, en combinaison avec l'lectrophysiologie. Nous avons identifi deux cellules inhibitrices de la rtine, les cellules horizontales et amacrines AII, qui bien que dpourvues de NMDARs, exprimaient des CP-AMPARs.Nous avons trouv que les CP-AMPARs taient prsents tous les stades du dveloppement.Pourtant, juste avant l'ouverture des yeux, ils ont prsent une rsistance pharmacologique la philanthotoxine (PhTX).Cette dcouverte tait inattendue vu que les polyamines synthtiques externes telles que la philanthotoxine sont habituellement utilises pour bloquer slectivement les CP-AMPARs.Curieusement, les rcepteurs insensibles aux polyamines taient absents des animaux levs dans le noir, dmontrant que la lumire pntrant l'oeil dclenche leur apparition.Cela se produit via une cascade dpendante du brain-derived neurotrophic factor (BDNF), puisque l'application de la neurotrophine rtablit la rsistance aux polyamines chez les animaux levs dans le noir.L'insensibilit aux polyamines des CP-AMPARs est suppose provenir de la prsence de la sousunit GluA2 dans les rcepteurs AMPA.Afin d'examiner cette possibilit, nous
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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) | 0.000 | 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 teacher head, 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".