C9orf72 deficiency contributes to synaptic hyperexcitability and excitotoxicity in frontotemporal dementia through CP‐AMPAR dysregulation
Bibliographic record
Abstract
BACKGROUND: Hexanucleotide repeat expansions in C9orf72, the most common genetic cause of frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), are associated with haploinsufficiency, synaptic dysfunction, and neurodegeneration. Synaptic hyperexcitability and excitotoxicity are emerging hallmarks in C9orf72-associated neurodegeneration; however, the underlying mechanisms in dementia-related pathology remain poorly understood. METHOD: Using C9orf72-knockout (C9-KO) mice as a model, we investigated the role of C9orf72 in synaptic function and excitotoxic vulnerability. We assessed hippocampal synaptic markers, including GluA1 surface expression, dendritic spine morphology, and calcium-permeable AMPA receptor (CP-AMPAR)-mediated plasticity. Kainic acid (KA)-induced excitotoxic stress was used to evaluate seizure susceptibility, network stability via EEG analysis, and hippocampal GluA1 dysregulation. CP-AMPAR antagonists were applied to examine their therapeutic potential. RESULT: C9-KO mice exhibited enhanced synaptic hyperexcitability, characterized by elevated surface GluA1 expression, reduced dendritic spine density, and enlarged spine heads in hippocampal neurons. These changes correlated with enhanced CP-AMPAR-mediated synaptic plasticity and heightened excitotoxic vulnerability following KA treatment. C9-KO mice displayed more severe seizures, abnormal EEG spectral power, and persistent hippocampal GluA1 elevation. Selective CP-AMPAR antagonism effectively reduced excitotoxic damage and normalized synaptic function. CONCLUSION: Our findings demonstrate that C9orf72 deficiency drives synaptic hyperexcitability and excitotoxic vulnerability through CP-AMPAR dysregulation, implicating this pathway in the pathophysiology of FTD. At the network level, C9orf72 loss amplifies excitatory signaling, linking synaptic dysfunction to network instability and neuronal degeneration. By identifying CP-AMPARs as central mediators of excitotoxicity, this study highlights a novel therapeutic target for C9orf72-associated dementia and other neurodegenerative diseases characterized by excitatory network dysfunction.
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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 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".