Super-resolution imaging reveals extrastriatal synaptic dysfunction in presymptomatic Huntington disease mice
Bibliographic record
Abstract
Synaptic structure and function are compromised prior to cell death and symptom onset in a variety of neurodegenerative diseases. In Huntington disease (HD), a CAG repeat expansion in the gene encoding the huntingtin protein results in a presymptomatic stage that typically spans multiple decades and is followed by striking degeneration of striatal tissue and the progression of debilitating motor symptoms. Many lines of evidence demonstrate that the HD presymptomatic window is associated with injurious effects to striatal synapses, many of which appear to be prerequisites to subsequent cell death. While the striatum is the most vulnerable region in the HD brain, it is widely recognized that HD is a brain-wide disease, affecting numerous extrastriatal regions that contribute to debilitating non-motor symptoms including cognitive dysfunction. Currently, we have a poor understanding of the synaptic integrity, or lack thereof, in extrastriatal regions in the presymptomatic HD brain. If early therapeutic intervention seeks to maintain healthy synaptic function, it is important to understand early HD-associated synaptopathy at a brain-wide, rather than striatal-exclusive, level. Here, we focused on the hippocampus as this structure is generally thought to be affected only in manifest HD despite the subtle cognitive deficits known to emerge in prodromal HD. We used super-resolution microscopy and multi-electrode array electrophysiology as sensitive measures of excitatory synapse structure and function, respectively, in the hippocampus of presymptomatic heterozygous HD mice (Q175FDN model). We found clear evidence for enhanced AMPA receptor subunit clustering and hyperexcitability well before the onset of a detectable HD-like behavioral phenotype. In addition, activity-dependent re-organization of synaptic protein nanostructure, and functional measures of synaptic plasticity were impaired in presymptomatic HD mice. These data demonstrate that synaptic abnormalities in the presymptomatic HD brain are not exclusive to the striatum, and highlight the need to better understand the region-dependent complexities of early synaptopathy in the HD brain.
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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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".