Article detail · 2019
Neuronal network dysfunction in a model for Kleefstra syndrome mediated by enhanced NMDAR signaling
- Year
- 2019
- Type
- article
Data source split
- YÖKSİS YÖKSİS article record
- YÖKSİS venue Nature Communications
- Catalog match (ISSN) Nature Communications
- OpenAlex OpenAlex enrichment (abstract, citations, topics)
Abstract
OpenAlex · English
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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Citations
OpenAlex cited_by_count. Not a WoS or Scopus citation count; those sources have no separate column here.
144 citations
OpenAlex cited_by_count (cache / database)