Hypersynchronous iPSC-derived SHANK2 neuronal networks are rescued by mGluR5 agonism
Bibliographic record
Abstract
Variants in the SHANK2 gene, linked to neurodevelopmental disorders like autism, were studied using human iPSC-derived neurons and multielectrode arrays. We compared two isogenic pairs of SHANK2 cell lines and found that SHANK2 networks exhibited a hyperconnectivity phenotype at the network level. These networks showed a significantly increased frequency and reduced duration of network burst events compared to controls. SHANK2 network activity was hypersynchronous, with stronger functional correlations between recording channels. Spikes within SHANK2 network bursts formed high-frequency trains, creating a distinctive burst shape. Calcium-dependent reverberating super bursts (RSBs) were common in control networks but rare in SHANK2 networks. Treatment with the group 1 mGluR agonist (S)-3,5-dihydroxyphenylglycine (DHPG) fully rescued SHANK2 network hypersynchrony, restored RSB detection, and improved network burst frequency and duration. The findings demonstrate that SHANK2 variants cause functional hyperconnectivity, which can be rescued by pharmacologically regulating glutamatergic neurotransmission.
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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 | 0.001 |
| Science and technology studies | 0.001 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| 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".