GluN2A Haploinsufficiency: a Novel Pre‐Clinical Model of Epilepsy
Bibliographic record
Abstract
N ‐methyl‐D‐aspartate receptors (NMDARs) are ionotropic glutamate receptors that play pivotal physiological roles during development and maturation of the mammalian central nervous system. Their functional diversity is controlled by nature of the two GluN2 subunits that co‐assemble with two GluN1 subunits in the receptor‐complex. Four GluN2 subunits exist (GluN2A–D) and their expression patterns are developmentally and spatially restricted. In the mammalian forebrain the predominant NMDAR composition is one of a diheteromeric assembly of two GluN1 with (i) two GluN2A subunits (GluN1/2A) or (ii) two GluN2B subunits (GluN1/2B) or a triheteromeric assembly of two GluN1 and one of each of a GluN2A and GluN2B subunit. The GluN2 identity strongly influences NMDAR kinetic behaviour – GluN1/2A and GluN1/2A/2B NMDARs have faster deactivation rates than those exhibited by GluN1/2B. Thus loss or reduced expression of GluN2A will change the kinetic profile of NMDAR populations. It is now recognized that humans who have certain mutations in GluN2A NMDAR subunits or are haploinsufficient for GluN2A protein experience epileptic seizures. To investigate the mechanistic basis of neuronal dysfunction associated with GluN2A reduction we have created a novel transgenic rat line using CRISPR/Cas9 technology, where exon 8 of GluN2 is deleted. We have studied the intrinsic and synaptic properties of hippocampal CA1 pyramidal neurons obtained from rats either completely lacking expression of Glun2A ( Grin2A −/− ) or ones which are heterozygous for the deletion ( Grin2A +/− ). Whole‐cell patch‐clamp recordings revealed that compared to recordings from wild‐type (WT) neurons no significant differences are observed in intrinsic excitability of either Grin2A +/− or Grin2A −/− pyramidal neurones when recordings were made from postnatal day 12–14 or postnatal day 28–32 animals. In addition, miniature and spontaneous excitatory and inhibitory synaptic currents recorded from either WT, Grin2A +/− or Grin2A −/− neurons showed little differences in the amplitudes or frequency of events. As is to be expected, however, loss of GluN2A expression leads to a slowing of the duration of the NMDAR‐mediated component of evoked synaptic currents. Our data also indicate that the magnitude of synaptic plasticity at Schaffer collateral/commissural synapses on to CA1 pyramidal neurons is reduced. Support or Funding Information Biotechnology and Biological Sciences Research Council BB/N015878/1 Epilepsy Research UK P1602 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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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 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.001 | 0.001 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
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".