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Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A

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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 Penn
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Communications Biology

ISSN

2399-3642

Publisher

Nature Research

Issue

1

Volume

5

Page range

1-17

Article number

a174

Department affiliated with

  • Informatics Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2022-03-02

First Open Access (FOA) Date

2022-03-02

First Compliant Deposit (FCD) Date

2022-03-01

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