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dc.contributor.authorBertocchi, Ilaria
dc.contributor.authorEltokhi, Ahmed
dc.contributor.authorRozov, Andrey
dc.contributor.authorNguyễn Chi, Vivan
dc.contributor.authorJensen, Vidar
dc.contributor.authorBus, Thorsten
dc.contributor.authorPawlak, Verena
dc.contributor.authorSerafino, Marta
dc.contributor.authorSonntag, Hannah
dc.contributor.authorYang, Boyi
dc.contributor.authorBurnashev, Nail
dc.contributor.authorLi, Shi-Bin
dc.contributor.authorObenhaus, Horst-Andreas
dc.contributor.authorBoth, Martin
dc.contributor.authorNiewoehner, Burkhard
dc.contributor.authorSingle, Frank N.
dc.contributor.authorBriese, Michael
dc.contributor.authorBoerner, Thomas
dc.contributor.authorGass, Peter
dc.contributor.authorRawlins, John Nick P.
dc.contributor.authorKöhr, Georg
dc.contributor.authorBannerman, David M.
dc.contributor.authorSprengel, Rolf
dc.date.accessioned2022-02-16T13:47:25Z
dc.date.available2022-02-16T13:47:25Z
dc.date.created2021-04-17T13:50:27Z
dc.date.issued2021
dc.identifier.citationCommunications Biology. 2021, 4 1-21.en_US
dc.identifier.issn2399-3642
dc.identifier.urihttps://hdl.handle.net/11250/2979432
dc.description.abstractThe NMDA receptor-mediated Ca2+ signaling during simultaneous pre- and postsynaptic activity is critically involved in synaptic plasticity and thus has a key role in the nervous system. In GRIN2-variant patients alterations of this coincidence detection provoked complex clinical phenotypes, ranging from reduced muscle strength to epileptic seizures and intellectual disability. By using our gene-targeted mouse line (Grin2aN615S), we show that voltage-independent glutamate-gated signaling of GluN2A-containing NMDA receptors is associated with NMDAR-dependent audiogenic seizures due to hyperexcitable midbrain circuits. In contrast, the NMDAR antagonist MK-801-induced c-Fos expression is reduced in the hippocampus. Likewise, the synchronization of theta- and gamma oscillatory activity is lowered during exploration, demonstrating reduced hippocampal activity. This is associated with exploratory hyperactivity and aberrantly increased and dysregulated levels of attention that can interfere with associative learning, in particular when relevant cues and reward outcomes are disconnected in space and time. Together, our findings provide (i) experimental evidence that the inherent voltage-dependent Ca2+ signaling of NMDA receptors is essential for maintaining appropriate responses to sensory stimuli and (ii) a mechanistic explanation for the neurological manifestations seen in the NMDAR-related human disorders with GRIN2 variant-meidiated intellectual disability and focal epilepsy.en_US
dc.language.isoengen_US
dc.publisherNatureen_US
dc.rightsNavngivelse 4.0 Internasjonal*
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/deed.no*
dc.titleVoltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in miceen_US
dc.typePeer revieweden_US
dc.typeJournal articleen_US
dc.description.versionpublishedVersionen_US
dc.source.pagenumber1-21en_US
dc.source.volume4en_US
dc.source.journalCommunications Biologyen_US
dc.identifier.doi10.1038/s42003-020-01538-4
dc.identifier.cristin1904783
cristin.ispublishedtrue
cristin.fulltextoriginal
cristin.qualitycode1


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