1-B-24 - Huntingtin reduction unmasks an active form of NMDAR-dependent synapse loss
Bibliographic record
Abstract
Authors: Jessica Barron¹, Matthew Parsons¹ ¹Memorial University of Newfoundland Abstract: Huntington disease (HD) is monogenic and caused by a CAG repeat expansion in the IT15 gene, which results in the production of a mutant huntingtin protein (mHTT). In addition to the production of this pathogenic variant, HD patients generate half the amount of wild type huntingtin (wtHTT). Although wtHTT has a well-established role in neurodevelopment, as its knockout is embryonic lethal, its exact role in the adult brain is not well understood. Recent literature suggests a major role for wtHTT in synaptic function in adult neurons, specifically loss of wtHTT impairs presynaptic vesicle release as well as postsynaptic receptor localization. We hypothesized that these synaptic impairments may lead to defects in NMDAR-dependent long term potentiation (LTP)-induced changes in hippocampal wtHTT-lowered neurons. Chemical LTP (cLTP) was induced using glycine in primary hippocampal cultured neurons and wtHTT levels were lowered by siRNA application. Both presynaptic synaptophysin (SYP) and postsynaptic PSD-95 were labelled by immunofluorescence. Using super-resolution microscopy, we quantified the density of SYP and PSD-95 puncta from individual dendrites at the nanoscale level. cLTP induction revealed an activity-dependant decrease in SYP, but not PSD-95, density in wtHTT-lowered cells. These findings indicate a potential switch from synaptic potentiation to depression and subsequent loss of synapses during hippocampal NMDAR activation due to wtHTT lowering. Understanding these outcomes is essential as many HD genetic therapies in development further lower patient wtHTT levels.
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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 | 0.002 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.002 | 0.003 |
| Science and technology studies | 0.000 | 0.003 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.002 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".