Age-dependent alterations in electrophysiological properties of corticomotor neurons in C9orf72 heterozygous mice
Bibliographic record
Abstract
ALS is the most common motor neuron disease in humans, whereby upper and lower motor neurons degenerate, eventually resulting in death. A major hypothesis underlying the mechanistic origin of neurodegeneration in ALS postulates that cortical hyperexcitability facilitates cell death. Previous research has identified the G4C2 hexanucleotide repeat expansion in the C9orf72 gene as the most common genetic cause of ALS; however, little is known about the contribution of the C9orf72 gene to neuronal excitability in the primary motor cortex. Thus, using a C9orf72 heterozygous loss-of-function (C9-Het LOF) mouse model, we assessed the action potential firing frequency of corticomotor neurons using whole-cell patch-clamp recordings made from an acute brain slice preparation. We have found that prior to disease onset, the action potential firing frequency is significantly lower in the C9-Het LOF mice compared to wildtype mice. In contrast, after disease onset, the action potential firing frequency is significantly higher in the C9-Het LOF mice compared to wildtype mice. These results highlight disease-stage-specific changes in cortical excitability. Moreover, we have found no change in spontaneous excitatory postsynaptic current frequency or amplitude at either disease stage, suggesting unaltered excitatory network function. Further investigation into the local inhibitory circuitry will reveal essential information about the neurophysiological mechanisms underlying neurodegeneration in C9orf72 ALS patients, which could contribute to the development of future therapeutic strategies.
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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 | 0.000 | 0.000 |
| 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".