Disruption of GRIN2B Impairs Differentiation in Human Neurons.

TitleDisruption of GRIN2B Impairs Differentiation in Human Neurons.
Publication TypeJournal Article
Year of Publication2018
AuthorsBell S, Maussion G, Jefri M, Peng H, Théroux J-F, Silveira H, Soubannier V, Wu H, Hu P, Galat E, S Torres-Platas G, Boudreau-Pinsonneault C, O'Leary LA, Galat V, Turecki G, Durcan TM, Fon EA, Mechawar N, Ernst C
JournalStem Cell Reports
Date Published2018 Jul 10

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.

Alternate JournalStem Cell Reports
PubMed ID29937144
PubMed Central IDPMC6067152