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

Monica Frega, Katrin Linda, Jason M. Keller, Güvem Gümüş-Akay, Britt Mossink, Jon-Ruben van Rhijn, Moritz Negwer, Teun Klein Gunnewiek, Katharina Foreman, Nine Kompier, Chantal Schoenmaker, Willem van den Akker, Ilse van der Werf, Astrid Oudakker, Huiqing Zhou, Tjitske Kleefstra, Dirk Schubert, Hans van Bokhoven and Nael Nadif Kasri ()
Additional contact information
Monica Frega: Donders Institute for Brain, Cognition, and Behaviour
Katrin Linda: Donders Institute for Brain, Cognition, and Behaviour
Jason M. Keller: Donders Institute for Brain, Cognition, and Behaviour
Güvem Gümüş-Akay: Donders Institute for Brain, Cognition, and Behaviour
Britt Mossink: Donders Institute for Brain, Cognition, and Behaviour
Jon-Ruben van Rhijn: Donders Institute for Brain, Cognition and Behaviour
Moritz Negwer: Donders Institute for Brain, Cognition, and Behaviour
Teun Klein Gunnewiek: Donders Institute for Brain, Cognition and Behaviour
Katharina Foreman: Donders Institute for Brain, Cognition and Behaviour
Nine Kompier: Donders Institute for Brain, Cognition and Behaviour
Chantal Schoenmaker: Donders Institute for Brain, Cognition, and Behaviour
Willem van den Akker: Donders Institute for Brain, Cognition, and Behaviour
Ilse van der Werf: Donders Institute for Brain, Cognition, and Behaviour
Astrid Oudakker: Donders Institute for Brain, Cognition, and Behaviour
Huiqing Zhou: Donders Institute for Brain, Cognition, and Behaviour
Tjitske Kleefstra: Donders Institute for Brain, Cognition, and Behaviour
Dirk Schubert: Donders Institute for Brain, Cognition and Behaviour
Hans van Bokhoven: Donders Institute for Brain, Cognition, and Behaviour
Nael Nadif Kasri: Donders Institute for Brain, Cognition, and Behaviour

Nature Communications, 2019, vol. 10, issue 1, 1-15

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-12947-3

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