Aberrant Synaptic Function in Mouse Models of Disease-associated GRIN1 Genetic Variants of the NMDA Receptor
Bibliographic record
Abstract
N-methyl-D-aspartate receptors (NMDARs) are tetrameric ligand-gated ion channels that participate in excitatory synaptic transmission by allowing Na+, K+, and Ca2+ to permeate through their channel. NMDARs are composed of two obligatory GluN1 subunits and two GluN2 (A-D) subunits. Therefore, mutations in the obligate GluN1 subunit can manifest as a wide-range of neurodevelopmental phenotypes, emphasizing the importance to investigate the underlying pathophysiology. Genetic variants in GRIN1, the gene encoding the GluN1 subunit, have been identified in a considerable number of individuals affected with GRIN variants through whole exome sequencing. Two such de novo missense variants in GRIN1, c.1858G>C/A and 2479G>C/A, result in the substitution of a glycine to an arginine at amino acid positions 620th (G620R) and 827th (G827R) of GluN1, respectively. Although functional analysis using recombinant systems has demonstrated deficits in NMDAR function, the impact of both variants on synaptic function in a native physiological context remains unknown. In this thesis, electrophysiological recordings – both extracellular field potential and whole-cell patch clamp – were made in acute hippocampal slices prepared from adult (8-12 weeks) transgenic mice mimicking the G620R and G827R missense variants found in patients in order to assess the physiological consequences of these Grin1 variants on NMDARs and synaptic functions. The Grin1-G620R variant significantly impaired NMDAR-mediated synaptic transmission and plasticity without affecting circuit formation or basal synaptic transmission in the CA1 hippocampus. Reduced NMDAR transmission caused by the Grin1-G620R variant was accompanied by reduced GluN2B activity and altered channel kinetics. However, Grin1-G620R did not affect NMDAR expression at the synapse or voltage-dependent magnesium block. The Grin1-G827R variant also significantly diminished NMDAR function. This phenotype was resulted from a reduced synaptic NMDAR expression, suggesting that GluN1-G827R containing NMDARs fail to assemble or traffic to the synapse. Interestingly, NMDAR dysfunction in Grin1-G827R variant mice was accompanied by an enhancement of presynaptic release probability.
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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 | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.002 |
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".