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

Elmasri, Marwa, Hunter, Daniel William, Winchester, Giles, Bates, Ella Emine, Aziz, Wajeeha, Van Der Does, Does Moolenaar, Karachaliou, Eirini, Sakimura, Kenji and Penn, Andrew Charles (2022) Common synaptic phenotypes arising from diverse mutations in the human NMDA receptor subunit GluN2A. Communications Biology, 5 (1). a174 1-17. ISSN 2399-3642

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Abstract

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.

Item Type: Article
Schools and Departments: School of Engineering and Informatics > Informatics
School of Life Sciences > Neuroscience
SWORD Depositor: Mx Elements Account
Depositing User: Mx Elements Account
Date Deposited: 02 Mar 2022 08:20
Last Modified: 02 Mar 2022 08:30
URI: http://sro.sussex.ac.uk/id/eprint/104651

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