Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling

• Published in: Nature communications Vol. 10; no. 1; pp. 4928 - 15
• Main Authors: Frega, Monica, Linda, Katrin, Keller, Jason M., Gümüş-Akay, Güvem, Mossink, Britt, van Rhijn, Jon-Ruben, Negwer, Moritz, Klein Gunnewiek, Teun, Foreman, Katharina, Kompier, Nine, Schoenmaker, Chantal, van den Akker, Willem, van der Werf, Ilse, Oudakker, Astrid, Zhou, Huiqing, Kleefstra, Tjitske, Schubert, Dirk, van Bokhoven, Hans, Nadif Kasri, Nael
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 30.10.2019; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 631/378/1689/2608; 631/378/340; 631/378/87; 64/60; 9/30; 9/74; Animals; Cerebral Cortex - cytology; Chromosome Deletion; Chromosomes, Human, Pair 9 - genetics; Chromosomes, Human, Pair 9 - metabolism; Cloning; Cognition & reasoning; Craniofacial Abnormalities - genetics; Craniofacial Abnormalities - metabolism; Disease Models, Animal; Dizocilpine Maleate - pharmacology; Excitatory Amino Acid Antagonists - pharmacology; Female; Genes; Glutamic acid receptors (ionotropic); Heart Defects, Congenital - genetics; Heart Defects, Congenital - metabolism; Histone methyltransferase; Histone-Lysine N-Methyltransferase - genetics; Histone-Lysine N-Methyltransferase - metabolism; Humanities and Social Sciences; Humans; Induced Pluripotent Stem Cells; Intellectual Disability - genetics; Intellectual Disability - metabolism; Loss of Function Mutation; Male; Mice; Morphology; multidisciplinary; Mutation; N-Methyl-D-aspartic acid receptors; Nerve Tissue Proteins - antagonists & inhibitors; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neural networks; Neurodevelopmental disorders; Neurogenesis; Neurons; Neurons - drug effects; Neurons - metabolism; Pathophysiology; Patients; Phenotypes; Pluripotency; Primary Cell Culture; Receptors, AMPA - metabolism; Receptors, N-Methyl-D-Aspartate - antagonists & inhibitors; Receptors, N-Methyl-D-Aspartate - genetics; Receptors, N-Methyl-D-Aspartate - metabolism; Science; Science (multidisciplinary); Up-Regulation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-12947-3

Kleefstra syndrome (KS) is a neurodevelopmental disorder caused by mutations in the histone methyltransferase EHMT1 . To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. Neuronal networks of patient-derived cells exhibit network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes are mediated by upregulation of NMDA receptor (NMDAR) subunit 1 correlating with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. In mice EHMT1 deficiency leads to similar neuronal network impairments with increased NMDAR function. Finally, we rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Summarized, we demonstrate a direct link between EHMT1 deficiency and NMDAR hyperfunction in human neurons, providing a potential basis for more targeted therapeutic approaches for KS. Kleefstra syndrome is a neurodevelopmental disorder associated with hapoinsufficiency of the histone methyltransferase EHMT1 . Here the authors show using induced pluripotent cells-derived neurons from patients that network dysfunction occurs and is due to dysfunction of the NMDA receptor.