Abstract
SummaryHeterozygous 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.
Highlights
N-Methyl-D-aspartic acid receptors (NMDARs) are widely expressed in neurons and are composed of different subunits that form specific types of functional glutamate receptors
Inclusion of GRIN2 subunits A–D varies depending on brain region and developmental time window (Monyer et al, 1994), where GRIN2B is present in embryonic NMDARs but is replaced in postnatal NMDARs by GRIN2A (Williams et al, 1993)
As neural progenitor cells (NPCs) differentiate, the ratio of GRIN2B/GRIN2A rises, while cells matured for 30 days have an expression profile closest to mouse subventricular zone radial precursor cells at embryonic day 13.5 (Figure S3)
Summary
N-Methyl-D-aspartic acid receptors (NMDARs) are widely expressed in neurons and are composed of different subunits that form specific types of functional glutamate receptors. Subunit expression patterns are often specific to developmental location or time window. Inclusion of GRIN2 subunits A–D varies depending on brain region and developmental time window (Monyer et al, 1994), where GRIN2B is present in embryonic NMDARs but is replaced in postnatal NMDARs by GRIN2A (Williams et al, 1993). The presence of GRIN2C likely occurs only in the cerebellum and after birth, and the presence GRIN3A and GRIN3B in NMDARs may influence synapse formation (Das et al, 1998). These consistent patterns of GRIN1–3 expression suggest tight regulatory control and highlight the tuning of NMDARs to signal different effects in a cell
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