Developmental Transformation of the Release Modality at the Calyx of Held Synapse
Bibliographic record
Abstract
Ca(2+) influx through voltage-gated Ca(2+) channels (VGCCs) into nerve terminals triggers vesicular fusion and neurotransmitter release. However, it is unknown whether the coupling between VGCCs and synaptic vesicles (SVs) is developmentally regulated. By paired patch-clamp recordings from the mouse calyx of Held synapse, we show here that injection of a Ca(2+) buffer with slow binding kinetics (EGTA; 10 mm) potently attenuated transmitter release in young terminals [postnatal day 8 (P8)-P12] but produced little effect in older ones (P16-P18), suggesting that SVs in young synapses are loosely coupled to VGCCs, but the coupling tightens spatially during maturation. Using voltage paradigms that specifically recruit different numbers of VGCCs without changing the driving force for Ca(2+), we found that the Ca(2+) cooperativity (m), estimated from graded presynaptic Ca(2+) currents and transmitter release, was much higher in P8-P12 synapses (m = 4.8-5.5) than that in P16-P18 synapses (m = 2.8-3.0; 1 mm [Ca(2+)](o)), implying that the number of VGCCs or Ca(2+) domains required for release of single SVs decreases with maturation. The m value remained significantly different between two age groups at 35 degrees C or in 2 mm [Ca(2+)](o) and was independent of postsynaptic receptor desensitization. We demonstrated that release from P8-P12 terminals involved both N- and P/Q-type VGCCs, but P/Q-type-associated release sites specifically displayed low m values. These results suggest a developmental transformation of the release modality from "microdomain," involving cooperative action of many loosely coupled N- and P/Q-type VGCCs, to "nanodomain," in which opening of fewer tightly coupled P/Q-type VGCCs effectively induce a fusion event. Spatial tightening improves the release efficiency and is likely a critical step for the development of high-fidelity neurotransmission in this and other central synapses.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.002 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.002 | 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".