Corticostriatal synaptic function in mouse models of Huntington's disease: early effects of huntingtin repeat length and protein load
Bibliographic record
Abstract
Huntington's disease (HD) is an autosomal dominant, late onset, neurodegenerative disease characterized by motor deficits and dementia that is caused by expansion of a CAG repeat in the HD gene. Clinical manifestations result from selective neuronal degeneration of predominantly GABAergic striatal medium-sized spiny neurons (MSNs). A growing number of studies demonstrate that personality, mood and cognitive disturbances are some of the earliest signs of HD and may reflect synaptic dysfunction prior to neuronal loss. Previous studies in striatal MSNs demonstrated early alterations in NMDA-type glutamate receptor currents in several HD mouse models, as well as evidence for presynaptic dysfunction prior to disease manifestations in the R6/2 HD fragment mouse model. We have compared corticostriatal synaptic function in full-length, human HD gene-carrying YAC transgenic mice expressing a non-pathogenic CAG repeat (YAC18; control) with three increasingly severe variants of pathogenic HD gene-expressing mice (YAC72 and two different lines of YAC128), at ages that precede any detectable disease phenotype. We report presynaptic dysfunction and a propensity towards synaptic depression in YAC72 and YAC128 compared to YAC18 mice, and, in the most severe model, we also observed altered AMPA receptor function. When normalized to evoked AMPAR currents, postsynaptic NMDAR currents are augmented in all three pathogenic HD YAC variants. These findings demonstrate multiple perturbations to corticostriatal synaptic function in HD mice, furthering our understanding of the early effects of the HD mutation that may contribute to cognitive dysfunction, mood disorders and later development of more serious dysfunction. Furthermore, this study provides a set of neurophysiological sequelae against which to test and compare other mouse models and potential therapies in HD.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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 | 0.000 |
| 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".