Disruption of GRIN2B Impairs Differentiation in Human Neurons

Scott Bell, Gilles Maussion, Malvin Jefri, Huashan Peng, Jean Francois Theroux, Heika Silveira, Vincent Soubannier, Hanrong Wu, Peng Hu, Ekaterina Galat, S. Gabriela Torres-Platas, Camille Boudreau-Pinsonneault, Liam A. O'Leary, Vasiliy Galat, Gustavo Turecki, Thomas M. Durcan, Edward A. Fon, Naguib Mechawar, Carl Ernst*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

Abstract

Heterozygous loss-of-function mutations in GRIN2B, a subunit of the NMDA receptor, cause intellectual disability and language impairment. We developed clonal models of GRIN2B deletion and loss-of-function mutations in a region coding for the glutamate binding domain in human cells and generated neurons from a patient harboring a missense mutation in the same domain. Transcriptome analysis revealed extensive increases in genes associated with cell proliferation and decreases in genes associated with neuron differentiation, a result supported by extensive protein analyses. Using electrophysiology and calcium imaging, we demonstrate that NMDA receptors are present on neural progenitor cells and that human mutations in GRIN2B can impair calcium influx and membrane depolarization even in a presumed undifferentiated cell state, highlighting an important role for non-synaptic NMDA receptors. It may be this function, in part, which underlies the neurological disease observed in patients with GRIN2B mutations. Mutations in GRIN2B cause intellectual disability and language impairments. In this study, Bell and colleagues engineer mutations in GRIN2B and repair a patient missense mutation to show an important role for GRIN2B and non-synaptic NMDA receptors in differentiating neural stem cells.

Original languageEnglish (US)
Pages (from-to)183-196
Number of pages14
JournalStem cell reports
Volume11
Issue number1
DOIs
StatePublished - Jul 10 2018

Keywords

  • CRISPR
  • CRISPR-Cas9
  • GRIN2B
  • NMDA
  • NMDAR2B
  • NPCs
  • glutamate
  • iPSCs
  • neural stem cell
  • neurodevelopment

ASJC Scopus subject areas

  • Biochemistry
  • Genetics
  • Developmental Biology
  • Cell Biology

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