Absence of GluN2A in hippocampal CA1 neurons leads to altered dendritic structure and reduced frequency of miniature excitatory synaptic events
Bibliographic record
Abstract
Abstract GluN2A is a NMDA receptor subunit postulated as important for learning and memory. In humans, heterozygous loss of function variants in the gene encoding it (GRIN2A) increase the risk of epilepsy, intellectual disability and schizophrenia. Haploinsufficient mouse models show electrophysiological abnormalities and thus to improve and widen understanding of the pathogenesis of GRIN2A-associated disorders in humans, this study aimed to assess the impact of Grin2a absence and haploinsufficiency on core neuronal and synaptic properties in genetically modified rats. Electrophysiological whole-cell current- and voltage-clamp recordings were made from CA1 pyramidal neurons in acute hippocampal slices from wild-type and Grin2a heterozygous (Grin2a+/−) and homozygous (Grin2a−/−) knock out rats aged postnatal day 27–34. While reduced levels or absence of GluN2A did not affect neuronal excitability or intrinsic membrane properties in both Grin2a+/− and Grin2a−/− rats, we found a reduced frequency of miniature excitatory post synaptic currents and a reduced density of proximal dendrites suggestive of a reduced number of excitatory synapses. Recordings from CA1 neurons in slices prepared from Grin2a+/− and Grin2a−/− rats revealed there was a reduced ratio of the current mediated by NMDA receptors compared to AMPA receptors, while in Grin2a−/− recordings, there was a slowing of the decay time-constant of the NMDA receptor-mediated excitatory postsynaptic currents. Moreover, neither summation of sub-threshold excitatory postsynaptic potentials nor summation of supra-threshold excitatory postsynaptic potentials to initiate action potential firing in CA1 pyramidal neurons indicated any dependence on GluN2A. We conclude that reduced levels of GluN2A alters the kinetics of NMDA receptor-mediated synaptic events and dendritic structure of CA1 neurons, but do not affect several other core neuronal functions. These relatively subtle changes are consistent with the largely intact neural functioning of the majority of humans carrying GRIN2A loss of function variants. Further research could explore whether the changes in synaptic properties we observed contribute to alterations in higher level circuit dynamics and computation, which may manifest as disorders of cognition and excitability in humans.
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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 | 0.003 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.002 | 0.001 |
| 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".