Summary: Researchers have identified a new molecular mechanism that may contribute to autism by altering early brain cell development.
Source: McGill University.
A study published in Stem Cell Reports by a McGill research team led by Dr. Carl Ernst at the Douglas Hospital Research Centre describes a previously unrecognized molecular role for the GRIN2B gene during early human brain development that may be relevant to autism.
Dr. Ernst, together with graduate student Scott Bell and collaborators Edward A. Fon and Thomas M. Durcan at the Montreal Neurological Institute and Hospital, used patient skin cells reprogrammed into neural cells to observe how a disease-causing mutation affects human neurons as they form. This patient-derived, human-cell approach allowed the researchers to follow the consequences of a GRIN2B mutation directly in human neural tissue grown in the laboratory.
The team concentrated on GRIN2B, a gene that encodes a subunit of the NMDA receptor. Mutations in one copy of GRIN2B are known to produce moderate intellectual disability and features of autism. While GRIN2B has typically been studied in the context of mature neurons—largely in animal models—the new findings show that GRIN2B protein is produced in human neural stem cells and has an important functional role much earlier in development than previously appreciated.
Producing electrically active human neurons from patient-derived stem cells provides a window into early human brain development in a controlled laboratory setting, even though these cells lack blood supply and the full complexity of a brain. According to Dr. Ernst, animal models such as mice do not fully recapitulate this genetic syndrome, so studying human cells is essential to uncover disease mechanisms specific to humans.
GRIN2B is a component of NMDA receptors, which are central to neuronal communication and synaptic function. The new data demonstrate that GRIN2B is also active in neural progenitor cells. Using genetic engineering, the researchers corrected the patient’s GRIN2B mutation in cultured cells and observed a reversal of the developmental defects, restoring cell behavior toward that of healthy control cells. This gene-repair experiment supports a causal link between GRIN2B dysfunction and impaired neuronal development.
Dr. Ernst emphasizes a “gene-first” strategy for studying autism spectrum disorders: rather than relying solely on clinical categories, researchers should investigate the specific genes responsible for neurodevelopmental syndromes. Autism encompasses many rare genetic disorders with overlapping symptoms; understanding each gene’s role can reveal convergent mechanisms and point to potential interventions.
The study’s findings suggest that other genes associated with autism—previously thought to act only in later stages of neuronal maturation—may also play critical roles during early neural stem cell stages. Future research should test whether additional autism-linked genes similarly influence early human neuron differentiation and function.
Funding: This research received support from the Canadian Institutes of Health Research, a Canada Research Chair Award, and the Sandra and Alain Bouchard Intellectual Disabilities Platform.
Source: Bruno Geoffroy – McGill University
Publisher: NeuroscienceNews.com organized this summary.
Image Source: NeuroscienceNews.com image in the public domain.
Original Research: Open access research article titled “Disruption of GRIN2B Impairs Differentiation in Human Neurons” by Scott Bell et al., published in Stem Cell Reports (June 21, 2018). DOI: 10.1016/j.stemcr.2018.05.0186
McGill University. New Insight Into How Autism Might Develop in the Brain. NeuroscienceNews, June 26, 2018.
Abstract
Disruption of GRIN2B Impairs Differentiation in Human Neurons
Highlights
- Non-synaptic NMDA receptors are crucial for development of forebrain neural stem cells.
- Mutations in GRIN2B impair neuronal differentiation.
- Genetic correction of patient cells restores proper differentiation.
- Pharmacological blockade of NMDA receptors also impairs differentiation.
Summary
Heterozygous loss-of-function mutations in GRIN2B, which encodes an NMDA receptor subunit, cause intellectual disability and language impairment. The authors developed clonal models of GRIN2B deletion and defined loss-of-function mutations in the glutamate-binding domain using human cells, and they generated neurons from a patient carrying a missense mutation in the same domain. Transcriptome analysis showed increased expression of genes associated with cell proliferation and decreased expression of genes linked to neuronal differentiation, consistent with extensive protein-level findings. Electrophysiology and calcium imaging revealed that NMDA receptors are present on neural progenitor cells and that human GRIN2B mutations can reduce calcium influx and membrane depolarization even in cells that are not yet fully differentiated. These results highlight an important early role for non-synaptic NMDA receptors and suggest that disruption of this function contributes to the neurological features seen in patients with GRIN2B mutations.