Impaired vocal communication, sleep‐related discharges, and transient alteration of slow‐wave sleep in developing mice lacking the GluN2A subunit of <i>N</i>‐methyl‐<scp>d</scp>‐aspartate receptors

Salmi, Manal; Gallo, Federico Del; Minlebaev, Marat; Захаров, А. В.; Pauly, Vanessa; Perron, Pauline; Pons-Bennaceur, Alexandre; Corby-Pellegrino, Séverine; Aniksztejn, Laurent; Lenck-Santini, Pierre-Pascal; Epsztein, Jérôme; Khazipov, Roustem; Burnashev, Nail; Bertini, Giuseppe; Szepetowski, Pierre

doi:10.1111/epi.16060

Cited by 24 publications

(20 citation statements)

References 53 publications

(145 reference statements)

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“…In addition, perisylvian, prefrontal, and cingulate cortices undergo a long developmental process and are sensitive to environmental influences and intrinsic physiological perturbations, as ED, throughout childhood and adolescence (57,58). GRIN2A knocked out mice, a genetic model of epilepsyaphasia spectrum (encompassing CECTS, Landau-Kleffner syndrome, and ESES), displayed impaired vocal communication as well as microstructural diffuse brain alteration in a specific development time window, corresponding to the human schoolage/pre-adolescence (59,60). In CECTS, morphometric analyses revealed diffuse increases in gray matter volumes that inversely correlated with age (49).…”

Section: The Age-dependence Effect Of Ed Density On Normal Neurodevelmentioning

confidence: 99%

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes

et al. 2019

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Childhood epilepsy with centrotemporal spikes (CECTS) is the most common type of "self-limited focal epilepsies." In its typical presentation, CECTS is a condition reflecting non-lesional cortical hyperexcitability of rolandic regions. The benign evolution of this disorder is challenged by the frequent observation of associated neuropsychological deficits and behavioral impairment. The abundance (or frequency) of interictal centrotemporal spikes (CTS) in CECTS is considered a risk factor for deficits in cognition. Herein, we captured the hemodynamic changes triggered by the CTS density measure (i.e., the number of CTS for time bin) obtained in a cohort of CECTS, studied by means of video electroencephalophy/functional MRI during quite wakefulness. We aim to demonstrate a direct influence of the diurnal CTS frequency on epileptogenic and cognitive networks of children with CECTS. A total number of 8,950 CTS (range between 27 and 801) were recorded in 23 CECTS (21 male), with a mean number of 255 CTS/patient and a mean density of CTS/30 s equal to 10,866 ± 11.46. Two independent general linear model models were created for each patient based on the effect of interest: "individual CTS" in model 1 and "CTS density" in model 2. Hemodynamic correlates of CTS density revealed the involvement of a widespread cortical-subcortical network encompassing the sensory-motor cortex, the Broca's area, the premotor cortex, the thalamus, the putamen, and red nucleus, while in the CTS event-related model, changes were limited to blood-oxygen-level-dependent (BOLD) signal increases in the sensory-motor cortices. A linear relationship was observed between the CTS density Vaudano et al. Hemodynamic Effects of CTS Density hemodynamic changes and both disease duration (positive correlation) and age (negative correlation) within the language network and the bilateral insular cortices. Our results strongly support the critical role of the CTS frequency, even during wakefulness, to interfere with the normal functioning of language brain networks.

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Section: The Age-dependence Effect Of Ed Density On Normal Neurodevelmentioning

confidence: 99%

Mapping the Effect of Interictal Epileptic Activity Density During Wakefulness on Brain Functioning in Focal Childhood Epilepsies With Centrotemporal Spikes

et al. 2019

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“…In animal models, homozygotes of targeted null GRIN2A exhibited jumpiness, increased locomotor activity, and loss of analgesic tolerance after repeated morphine doses ( Sakimura et al, 1995 ; Kadotani et al, 1996 ). In Grin2a knockout mice, spontaneous epileptiform discharges were detected ( Salmi et al, 2018 , 2019 ). These clues indicated that loss of GluN2A protein was associated with increased neuronal excitability.…”

Section: Discussionmentioning

confidence: 99%

GRIN2A Variants Associated With Idiopathic Generalized Epilepsies

Liu

Lin

et al. 2021

Front. Mol. Neurosci.

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Objective: The objective of this study is to explore the role of GRIN2A gene in idiopathic generalized epilepsies and the potential underlying mechanism for phenotypic variation.Methods: Whole-exome sequencing was performed in a cohort of 88 patients with idiopathic generalized epilepsies. Electro-physiological alterations of the recombinant N-methyl-D-aspartate receptors (NMDARs) containing GluN2A mutants were examined using two-electrode voltage-clamp recordings. The alterations of protein expression were detected by immunofluorescence staining and biotinylation. Previous studies reported that epilepsy related GRIN2A missense mutations were reviewed. The correlation among phenotypes, functional alterations, and molecular locations was analyzed.Results: Three novel heterozygous missense GRIN2A mutations (c.1770A > C/p.K590N, c.2636A > G/p.K879R, and c.3199C > T/p.R1067W) were identified in three unrelated cases. Electrophysiological analysis demonstrated R1067W significantly increased the current density of GluN1/GluN2A NMDARs. Immunofluorescence staining indicated GluN2A mutants had abundant distribution in the membrane and cytoplasm. Western blotting showed the ratios of surface and total expression of the three GluN2A-mutants were significantly increased comparing to the wild type. Further analysis on the reported missense mutations demonstrated that mutations with severe gain-of-function were associated with epileptic encephalopathy, while mutations with mild gain of function were associated with mild phenotypes, suggesting a quantitative correlation between gain-of-function and phenotypic severity. The mutations located around transmembrane domains were more frequently associated with severe phenotypes and absence seizure-related mutations were mostly located in carboxyl-terminal domain, suggesting molecular sub-regional effects.Significance: This study revealed GRIN2A gene was potentially a candidate pathogenic gene of idiopathic generalized epilepsies. The functional quantitative correlation and the molecular sub-regional implication of mutations helped in explaining the relatively mild clinical phenotypes and incomplete penetrance associated with GRIN2A variants.

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“…It has been found that androgen receptor (Ar) in the main circadian clock of suprachiasmatic nucleus regulates the effect of light on male activity [ 47 ]. In addition, changes in GluN2A, a N-methyl-d-aspartate receptor (NMDAR) subunit encoded by GRIN2A, are associated with neurodevelopmental disorders and are critical to sleep-related physiological and pathological processes [ 48 , 49 ]. The aforementioned analysis showed that berberine can achieve therapeutic effect by influencing the expression of key disorder factors.…”

Section: Discussionmentioning

confidence: 99%