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Impaired vocal communication, sleep‐related discharges, and transient alteration of slow‐wave sleep in developing mice lacking the GluN2A subunit of N ‐methyl‐ d ‐aspartate receptors
Author(s) -
Salmi Manal,
Del Gallo Federico,
Minlebaev Marat,
Zakharov Andrey,
Pauly Vanessa,
Perron Pauline,
PonsBennaceur Alexandre,
CorbyPellegrino Séverine,
Aniksztejn Laurent,
LenckSantini PierrePascal,
Epsztein Jérôme,
Khazipov Rustem,
Burnashev Nail,
Bertini Giuseppe,
Szepetowski Pierre
Publication year - 2019
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.16060
Subject(s) - nmda receptor , slow wave sleep , epilepsy , neuroscience , electroencephalography , spike and wave , glutamate receptor , sleep (system call) , psychology , endocrinology , receptor , medicine , chemistry , computer science , operating system
Objective Glutamate‐gated N ‐methyl‐ d ‐aspartate receptors ( NMDAR s) are instrumental to brain development and functioning. Defects in the GRIN 2A gene, encoding the GluN2A subunit of NMDAR s, cause slow‐wave sleep ( SWS )‐related disorders of the epilepsy‐aphasia spectrum ( EAS ). The as‐yet poorly understood developmental sequence of early EAS ‐related phenotypes, and the role of GluN2A‐containing NMDAR s in the development of SWS and associated electroencephalographic ( EEG ) activity patterns, were investigated in Grin2a knockout ( KO ) mice. Methods Early social communication was investigated by ultrasonic vocalization ( USV ) recordings; the relationship of electrical activity of the cerebral cortex with SWS was studied using deep local field potential or chronic EEG recordings at various postnatal stages. Results Grin2a KO pups displayed altered USV and increased occurrence of high‐voltage spindles. The pattern of slow‐wave activity induced by low‐dose isoflurane was altered in Grin2a KO mice in the 3rd postnatal week and at 1 month of age. These alterations included strong suppression of the delta oscillation power and an increase in the occurrence of the spike‐wave bursts. The proportion of SWS and the sleep quality were transiently reduced in Grin2a KO mice aged 1 month but recovered by the age of 2 months. Grin2a KO mice also displayed spontaneous spike‐wave discharges, which occurred nearly exclusively during SWS , at 1 and 2 months of age. Significance The impaired vocal communication, the spike‐wave discharges occurring almost exclusively in SWS , and the age‐dependent alteration of SWS that were all seen in Grin2a KO mice matched the sleep‐related and age‐dependent manifestations seen in children with EAS , hence validating the Grin2a KO as a reliable model of EAS disorders. Our data also show that GluN2A‐containing NMDAR s are involved in slow‐wave activity, and that the period of postnatal brain development (postnatal day 30) when several anomalies peaked might be critical for GluN2A‐dependent, sleep‐related physiological and pathological processes.