Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
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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.
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For some of these monogenic syndromes it has recently been shown that deficits in the structural development of the PFC underlie these problems.
“For some of these syndromes it has recently been shown that deficits in the structural development of the PFC underlie these problems [281–287].”
From Development of prefrontal cortex (2022) · cites this paper as [282]
In Results, under “Single-cell level characterization of KS neurons” (page unavailable), the paper reports no significant differences in somatodendritic morphology between Kleefstra-syndrome and control cortical neurons. It studies neuronal network dysfunction, not structural development of the PFC, and therefore does not show that PFC structural deficits underlie the problems described. (LLM, conf=0.88)
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- Authors
- Frega, M., Linda, K., Keller, J. M., Gümüş-Akay, G., Mossink, B., van Rhijn, J.-R., Negwer, M., Klein Gunnewiek, T., Foreman, K., Kompier, N., Schoenmaker, C., van den Akker, W., van der Werf, I., Oudakker, A., Zhou, H., Kleefstra, T., Schubert, D., van Bokhoven, H., & Nadif Kasri, N.
- Affiliations
- Radboud University Medical Center (NL)
- Radboud University Nijmegen (NL)
- ORCID
- Venue
- Nature Communications
- Published
- 2019-10-30
- Volume
- 10
- Issue
- 1
- Pages
- 4928-4928
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC6821803
- OpenAlex
- W2982393021
- Cited by
- 137
- References
- 64
- Citations by year
- 2026: 13 · 2025: 12 · 2024: 17 · 2023: 20 · 2022: 23 · 2021: 23 · 2020: 25 · 2019: 2 · 2018: 1
- FWCI
- 11.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Radboud Repository (Radboud University) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- RePEc: Research Papers in Economics (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- CINECA IRIS Institutial Research Information System (University of Genoa) (submittedVersion)
- University of Twente Research Information (submittedVersion, cc-by)
- Funders
- ZonMw (91718310, 91217055)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (ALW2PJ/13082)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Keywords
- Kleefstra syndrome, EHMT1, NMDA receptor, NMDAR1, neuronal network dysfunction, cortical excitatory neurons, induced pluripotent stem cells, H3K9me2, histone methyltransferase, neurodevelopmental disorders, NMDA receptor blockade, iPSC-derived neurons
- MeSH terms
- Loss of Function Mutation, Animals, Cerebral Cortex, Chromosome Deletion, Chromosomes, Human, Pair 9, Disease Models, Animal, Female, Heart Defects, Congenital, Humans, Male, Intellectual Disability, Nerve Tissue Proteins, Neurons, Histone-Lysine N-Methyltransferase, Up-Regulation, Receptors, N-Methyl-D-Aspartate, Dizocilpine Maleate, Receptors, AMPA, Excitatory Amino Acid Antagonists, Craniofacial Abnormalities, Mice, Induced Pluripotent Stem Cells, Primary Cell Culture
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