s42003-022-03115-3.pdf (5.18 MB)
Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A
Version 2 2023-06-12, 07:42
Version 1 2023-06-10, 02:46
journal contribution
posted on 2023-06-12, 07:42 authored by Marwa Elmasri, Daniel William Hunter, Giles WinchesterGiles Winchester, Ella Bates, Wajeeha AzizWajeeha Aziz, Does Moolenaar Van Der Does, Eirini Karachaliou, Kenji Sakimura, Andrew PennAndrew PennDominant 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.
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- Published
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Communications BiologyISSN
2399-3642Publisher
Nature ResearchExternal DOI
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1Volume
5Page range
1-17Article number
a174Department affiliated with
- Informatics Publications
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- Yes
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- Yes
Legacy Posted Date
2022-03-02First Open Access (FOA) Date
2022-03-02First Compliant Deposit (FCD) Date
2022-03-01Usage metrics
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