Related Experiment Video
Updated: Jul 25, 2025
Rapid Detection of Neurodevelopmental Phenotypes in Human Neural Precursor Cells NPCs
Published on: March 2, 2018
Schizophrenia-associated NRXN1 deletions induce developmental-timing- and cell-type-specific vulnerabilities in human
Rebecca Sebastian1,2, Kang Jin3,4, Narciso Pavon2
1Graduate Program in Neuroscience & Behavior, UMass Amherst, Amherst, MA, 01003, USA.
Abstract:
De novo mutations and copy number deletions in NRXN1 (2p16.3) pose a significant risk for schizophrenia (SCZ). It is unclear how NRXN1 deletions impact cortical development in a cell type-specific manner and disease background modulates these phenotypes. Here, we leveraged human pluripotent stem cell-derived forebrain organoid models carrying NRXN1 heterozygous deletions in isogenic and SCZ patient genetic backgrounds and conducted single-cell transcriptomic analysis over the course of brain organoid development from 3 weeks to 3.5 months. Intriguingly, while both deletions similarly impacted molecular pathways associated with ubiquitin-proteasome system, alternative splicing, and synaptic signaling in maturing glutamatergic and GABAergic neurons, SCZ-NRXN1 deletions specifically perturbed developmental trajectories of early neural progenitors and accumulated disease-specific transcriptomic signatures. Using calcium imaging, we found that both deletions led to long-lasting changes in spontaneous and synchronous neuronal networks, implicating synaptic dysfunction. Our study reveals developmental-timing- and cell-type-dependent actions of NRXN1 deletions in unique genetic contexts.
Insights
Neurexin-1 (NRXN1) deletions impact brain development and neuronal networks. Schizophrenia (SCZ) patient backgrounds reveal specific disruptions in neural progenitors and unique molecular signatures, affecting cortical development.
Area of Science:
- Neuroscience
- Developmental Biology
- Genetics
Background:
- Deletions in the NRXN1 gene are linked to schizophrenia risk.
- The precise effects of NRXN1 deletions on cortical development and how genetic background influences these are not fully understood.
Purpose of the Study:
- To investigate the cell-type-specific impact of NRXN1 deletions on human forebrain development.
- To explore how genetic background, including schizophrenia (SCZ) patient mutations, modulates these effects.
Main Methods:
- Utilized human pluripotent stem cell-derived forebrain organoids with NRXN1 heterozygous deletions.
- Employed single-cell transcriptomic analysis across developmental timepoints (3 weeks to 3.5 months).
- Conducted calcium imaging to assess neuronal network activity.
Main Results:
- Both NRXN1 deletions affected ubiquitin-proteasome system, splicing, and synaptic signaling in mature neurons.
- SCZ-associated NRXN1 deletions uniquely altered early neural progenitor development and accumulated disease-specific gene expression.
- Calcium imaging revealed lasting alterations in neuronal network function, suggesting synaptic dysfunction.
Conclusions:
- NRXN1 deletions have distinct effects on cortical development dependent on developmental timing and cell type.
- Genetic context, particularly SCZ-related backgrounds, significantly shapes the phenotypic consequences of NRXN1 deletions.
- Findings highlight NRXN1's critical role in neurodevelopment and synaptic function relevant to schizophrenia.
More Related Videos
08:22A Novel Strategy Combining Array-CGH, Whole-exome Sequencing and In Utero Electroporation in Rodents to Identify Causative Genes for Brain Malformations
Published on: December 1, 2017
07:40Generation of iPSC-derived Human Brain Organoids to Model Early Neurodevelopmental Disorders
Published on: April 14, 2017
