Hypersynchronous iPSC-derived <i>SHANK2</i> neuronal networks are rescued by mGluR5 agonism
Bibliographic record
Abstract
ABSTRACT Variants in the gene encoding the postsynaptic scaffolding protein SHANK2 are associated with several neurodevelopmental disorders, including autism spectrum disorder. Here, we used in vitro multielectrode arrays and pharmacological manipulations to characterize how functional connectivity and network-level firing properties were altered in cultures of human iPSC-derived SHANK2 neurons. Using two isogenic pairs of SHANK2 cell lines, we showed that the SHANK2 hyperconnectivity phenotype was recapitulated at the network level. SHANK2 networks displayed significantly increased frequency and reduced duration of network burst events relative to controls. SHANK2 network activity was hypersynchronous, with increased functional correlation strength between recording channels. Analysis of intra-network burst firing dynamics revealed that spikes within SHANK2 network bursts were organized into high-frequency trains, producing a distinctive network burst shape. Calcium-dependent events called reverberating super bursts (RSBs) were observed in control networks but rarely occurred in SHANK2 networks. SHANK2 network hypersynchrony and numbers of strong correlations were fully rescued by the group 1 mGluR agonist DHPG, that also restored detection of RSBs and significantly improved network burst frequency and duration metrics. Our results demonstrate that SHANK2 variants produce a functional hyperconnectivity phenotype that deviates from the developmental trajectory of isogenic control networks. Furthermore, the hypersynchronous phenotype was 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 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.002 | 0.002 |
| Research integrity | 0.001 | 0.003 |
| 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".