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  Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice

Bertocchi, I., Eltokhi, A., Rozov, A., Chi, V. N., Jensen, V., Bus, T., et al. (2021). Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice. Communications Biology, 4: 59 (2021), pp. 1-21. doi:10.1038/s42003-020-01538-4.

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Item Permalink: http://hdl.handle.net/21.11116/0000-0007-B21B-2 Version Permalink: http://hdl.handle.net/21.11116/0000-0008-006B-0
Genre: Journal Article
Alternative Title : Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice

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 Creators:
Bertocchi, Ilaria1, Author              
Eltokhi, Ahmed2, Author              
Rozov, Andrej1, Author              
Chi, Vivan Nguyễn, Author
Jensen, Vidar, Author
Bus, Thorsten1, Author              
Pawlak, Verena1, Author              
Serafino, Marta1, Author              
Sonntag, Hannah1, Author              
Yang, Boyi1, Author              
Burnashev, Nail1, Author              
Li, Shi-Bin1, Author              
Obenhaus, Horst A.1, Author              
Both, Martin, Author
Niewoehner, Burkhard, Author
Single, Frank N.1, Author              
Briese, Michael, Author
Boerner, Thomas, Author
Gass, Peter, Author
Rawlins, John Nick P., Author
Köhr, Georg1, Author              Bannerman, David M, AuthorSprengel, Rolf1, Author               more..
Affiliations:
1Department of Molecular Neurobiology, Max Planck Institute for Medical Research, Max Planck Society, ou_1497704              
2Max Planck Institute for Medical Research, Max Planck Society, ou_1125545              

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 Abstract: The 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.

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Language(s): eng - English
 Dates: 2020-05-082020-11-202021-01-08
 Publication Status: Published online
 Pages: 21
 Publishing info: -
 Table of Contents: -
 Rev. Type: Peer
 Identifiers: DOI: 10.1038/s42003-020-01538-4
 Degree: -

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Title: Communications Biology
Source Genre: Journal
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Publ. Info: London : Springer Nature
Pages: - Volume / Issue: 4 Sequence Number: 59 (2021) Start / End Page: 1 - 21 Identifier: ISSN: 2399-3642
CoNE: https://pure.mpg.de/cone/journals/resource/2399-3642