Axonal ER Ca<sup>2+</sup>Release Selectively Enhances Activity-Independent Glutamate Release in a Huntington Disease Model
Bibliographic record
Abstract
Action potential-independent (miniature) neurotransmission occurs at all chemical synapses, but remains poorly understood, particularly in pathological contexts. Axonal endoplasmic reticulum (ER) Ca2+stores are thought to influence miniature neurotransmission, and aberrant ER Ca2+handling is implicated in progression of Huntington disease (HD). Here, we report elevated miniature excitatory postsynaptic current (mEPSC) frequencies in recordings from YAC128 mouse (HD-model) neurons (from cortical cultures and striatum-containing brain slices – both from male and female animals). Pharmacological experiments suggest this is mediated indirectly by enhanced tonic ER Ca2+release. Calcium imaging, using an axon-localized sensor, revealed slow action potential (AP)-independent ER Ca2+release waves in both YAC128 and wild-type cultures. These Ca2+waves occurred at similar frequencies in both genotypes, but spread less extensively and were of lower amplitude in YAC128 axons, consistent with axonal ER Ca2+store depletion. Surprisingly, basal cytosolic Ca2+levels were lower in YAC128 boutons and YAC128 mEPSCs were less sensitive to intracellular Ca2+chelation. Together, these data suggest elevated miniature glutamate release in YAC128 cultures is associated with axonal ER Ca2+depletion but not directly mediated by ER Ca2+release into the cytoplasm. In contrast to increased mEPSC frequencies, cultured YAC128 cortical neurons showed less frequent AP-dependent (spontaneous) Ca2+events in soma and axons, although evoked glutamate release detected by iGluSnFR in brain slices was similar between genotypes. Our results indicate axonal ER dysfunction selectively elevates miniature glutamate release from cortical terminals in HD. This, together with reduced spontaneous cortical neuron firing, may cause a shift from activity-dependent to -independent glutamate release in HD, with potential implications for fidelity and plasticity of cortical excitatory signaling. Significance statement Miniature neurotransmitter release persists at all chemical neuronal synapses in the absence of action potential firing but remains poorly understood, particularly in disease states. We show enhanced miniature glutamate release from cortical neurons in the YAC128 mouse Huntington disease model. This effect is mediated by axonal ER Ca2+store depletion, but is not obviously due to elevated ER-to-cytosol Ca2+release. Conversely, YAC128 cortical pyramidal neurons fired fewer action potentials and evoked cortical glutamate release was similar between WT an YAC128 preparations, indicating axonal ER depletion selectively enhances miniature glutamate release in YAC128 mice. These results extend our understanding of action potential independent neurotransmission and highlight a potential involvement of elevated miniature glutamate release in Huntington disease pathology.
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.001 | 0.001 |
| 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".