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Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice
The NMDA receptor-mediated Ca(2+) 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, rangin...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794508/ https://www.ncbi.nlm.nih.gov/pubmed/33420383 http://dx.doi.org/10.1038/s42003-020-01538-4 |
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author | Bertocchi, Ilaria Eltokhi, Ahmed Rozov, Andrey Chi, Vivan Nguyễn Jensen, Vidar Bus, Thorsten Pawlak, Verena Serafino, Marta Sonntag, Hannah Yang, Boyi Burnashev, Nail Li, Shi-Bin Obenhaus, Horst A. Both, Martin Niewoehner, Burkhard Single, Frank N. Briese, Michael Boerner, Thomas Gass, Peter Rawlins, John Nick P. Köhr, Georg Bannerman, David M. Sprengel, Rolf |
author_facet | Bertocchi, Ilaria Eltokhi, Ahmed Rozov, Andrey Chi, Vivan Nguyễn Jensen, Vidar Bus, Thorsten Pawlak, Verena Serafino, Marta Sonntag, Hannah Yang, Boyi Burnashev, Nail Li, Shi-Bin Obenhaus, Horst A. Both, Martin Niewoehner, Burkhard Single, Frank N. Briese, Michael Boerner, Thomas Gass, Peter Rawlins, John Nick P. Köhr, Georg Bannerman, David M. Sprengel, Rolf |
author_sort | Bertocchi, Ilaria |
collection | PubMed |
description | The NMDA receptor-mediated Ca(2+) 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 (Grin2a(N615S)), 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 Ca(2+) 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. |
format | Online Article Text |
id | pubmed-7794508 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-77945082021-01-21 Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice Bertocchi, Ilaria Eltokhi, Ahmed Rozov, Andrey Chi, Vivan Nguyễn Jensen, Vidar Bus, Thorsten Pawlak, Verena Serafino, Marta Sonntag, Hannah Yang, Boyi Burnashev, Nail Li, Shi-Bin Obenhaus, Horst A. Both, Martin Niewoehner, Burkhard Single, Frank N. Briese, Michael Boerner, Thomas Gass, Peter Rawlins, John Nick P. Köhr, Georg Bannerman, David M. Sprengel, Rolf Commun Biol Article The NMDA receptor-mediated Ca(2+) 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 (Grin2a(N615S)), 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 Ca(2+) 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. Nature Publishing Group UK 2021-01-08 /pmc/articles/PMC7794508/ /pubmed/33420383 http://dx.doi.org/10.1038/s42003-020-01538-4 Text en © The Author(s) 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Bertocchi, Ilaria Eltokhi, Ahmed Rozov, Andrey Chi, Vivan Nguyễn Jensen, Vidar Bus, Thorsten Pawlak, Verena Serafino, Marta Sonntag, Hannah Yang, Boyi Burnashev, Nail Li, Shi-Bin Obenhaus, Horst A. Both, Martin Niewoehner, Burkhard Single, Frank N. Briese, Michael Boerner, Thomas Gass, Peter Rawlins, John Nick P. Köhr, Georg Bannerman, David M. Sprengel, Rolf Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
title | Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
title_full | Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
title_fullStr | Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
title_full_unstemmed | Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
title_short | Voltage-independent GluN2A-type NMDA receptor Ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
title_sort | voltage-independent glun2a-type nmda receptor ca(2+) signaling promotes audiogenic seizures, attentional and cognitive deficits in mice |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794508/ https://www.ncbi.nlm.nih.gov/pubmed/33420383 http://dx.doi.org/10.1038/s42003-020-01538-4 |
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