Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A.
Journal
Communications biology
ISSN: 2399-3642
Titre abrégé: Commun Biol
Pays: England
ID NLM: 101719179
Informations de publication
Date de publication:
28 02 2022
28 02 2022
Historique:
received:
03
09
2020
accepted:
31
01
2022
entrez:
1
3
2022
pubmed:
2
3
2022
medline:
5
4
2022
Statut:
epublish
Résumé
Dominant mutations in the human gene GRIN2A, encoding NMDA receptor (NMDAR) subunit GluN2A, make a significant and growing contribution to the catalogue of published single-gene epilepsies. Understanding the disease mechanism in these epilepsy patients is complicated by the surprising diversity of effects that the mutations have on NMDARs. Here we have examined the cell-autonomous effect of five GluN2A mutations, 3 loss-of-function and 2 gain-of-function, on evoked NMDAR-mediated synaptic currents (NMDA-EPSCs) in CA1 pyramidal neurons in cultured hippocampal slices. Despite the mutants differing in their functional incorporation at synapses, prolonged NMDA-EPSC current decays (with only marginal changes in charge transfer) were a common effect for both gain- and loss-of-function mutants. Modelling NMDA-EPSCs with mutant properties in a CA1 neuron revealed that the effect of GRIN2A mutations can lead to abnormal temporal integration and spine calcium dynamics during trains of concerted synaptic activity. Investigations beyond establishing the molecular defects of GluN2A mutants are much needed to understand their impact on synaptic transmission.
Identifiants
pubmed: 35228668
doi: 10.1038/s42003-022-03115-3
pii: 10.1038/s42003-022-03115-3
pmc: PMC8885697
doi:
Substances chimiques
Receptors, N-Methyl-D-Aspartate
0
N-methyl D-aspartate receptor subtype 2A
VH92ICR8HX
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
174Subventions
Organisme : RCUK | Medical Research Council (MRC)
ID : MR/M020746/1
Informations de copyright
© 2022. The Author(s).
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