Journal article
Voltage-independent GluN2A-type NMDA receptor Ca2+ signaling promotes audiogenic seizures, attentional and cognitive deficits in mice.
- 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Corrected version of record, pdf, 3.3MB, Terms of use)
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- Publisher copy:
- 10.1038/s42003-020-01538-4
Authors
- Publisher:
- Springer Nature
- Journal:
- Communications Biology More from this journal
- Volume:
- 4
- Issue:
- 1
- Article number:
- 59
- Publication date:
- 2021-01-08
- Acceptance date:
- 2020-11-20
- DOI:
- EISSN:
-
2399-3642
- Pmid:
-
33420383
- Language:
-
English
- Keywords:
- Pubs id:
-
1156546
- Local pid:
-
pubs:1156546
- Deposit date:
-
2021-02-19
- ARK identifier:
Terms of use
- Copyright holder:
- Bertocchi et al.
- Copyright date:
- 2021
- Rights statement:
- ©2021 The Author(s), corrected publication 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/.
- Notes:
-
A correction to this article is available at: 10.1038/s42003-021-01717-x
- Licence:
- CC Attribution (CC BY)
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