ArticleGenome medicine2023
Morphological and transcriptomic analyses of stem cell-derived cortical neurons reveal mechanisms underlying synaptic dysfunction in schizophrenia.
Article in Genome medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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14 citing papers in PubMed, 22 citations in OpenAlex.
- Primary cilia and neural computation.Journal of biomedical science · 2026Review
- How copy number variations shape brain developmental disorders: Unraveling the synaptic puzzle.Psychiatry and clinical neurosciences · 2026Review
- Descriptive transcriptomic profiling differentiates oral leukoplakia from proliferative verrucous leukoplakia and reveals distinct molecular signatures.Medicina oral, patologia oral y cirugia bucal · 2026Article
- Integrated protocol for concurrent generation of microglial and neuronal cells in human cerebral organoids.BMC methods · 2026Article
- Repeated Clozapine Administration Causes Extensive Changes to the Expression of Coding and Non-coding RNAs, Including miR-124, in the Mouse Frontal Cortex.Molecular neurobiology · 2025Article
- Engineering Cortical Networks: An Open Platform for Controlled Human Circuit Formation and Synaptic Analysis In Vitro.Advanced healthcare materials · 2025Article
- Brain-Derived Neurotrophic Factor Trafficking via the Regulated Secretory Pathway: Mechanisms and Disease Implications.Molecular neurobiology · 2025Review
- Analyses of GWAS and Sub-Threshold Loci Lead to the Discovery of Dendrite Development and Morphology Dysfunction Underlying Schizophrenia Genetic Risk.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Whole-exome sequencing analysis identifies risk genes for schizophrenia.Nature communications · 2025Article
- Effects of Complex I Inhibition on the Architecture of Neural Rosettes Differentiated from Human-Induced Pluripotent Stem Cells.Stem cells and development · 2025Article
- Shared genetic architecture and causal relationship between frailty and schizophrenia.Schizophrenia (Heidelberg, Germany) · 2025Article
- Accelerated pace of frailty in patients with schizophrenia.The journal of nutrition, health & aging · 2025Article
- Model systems for emulating human tissue and physiology in psychiatric research.Frontiers in neuroscience · 2025Review
- Harnessing stem cell-based approaches for clinically meaningful discoveries in schizophrenia.Schizophrenia research · 2024Article
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4 authors at 1 institution in 1 country.
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Abstract
backgroundPostmortem studies in schizophrenia consistently show reduced dendritic spines in the cerebral cortex but the mechanistic underpinnings of these deficits remain unknown. Recent genome-wide association studies and exome sequencing investigations implicate synaptic genes and processes in the disease biology of schizophrenia.
methodsWe generated human cortical pyramidal neurons by differentiating iPSCs of seven schizophrenia patients and seven healthy subjects, quantified dendritic spines and synapses in different cortical neuron subtypes, and carried out transcriptomic studies to identify differentially regulated genes and aberrant cellular processes in schizophrenia.
resultsCortical neurons expressing layer III marker CUX1, but not those expressing layer V marker CTIP2, showed significant reduction in dendritic spine density in schizophrenia, mirroring findings in postmortem studies. Transcriptomic experiments in iPSC-derived cortical neurons showed that differentially expressed genes in schizophrenia were enriched for genes implicated in schizophrenia in genome-wide association and exome sequencing studies. Moreover, most of the differentially expressed genes implicated in schizophrenia genetic studies had lower expression levels in schizophrenia cortical neurons. Network analysis of differentially expressed genes led to identification of NRXN3 as a hub gene, and follow-up experiments showed specific reduction of the NRXN3 204 isoform in schizophrenia neurons. Furthermore, overexpression of the NRXN3 204 isoform in schizophrenia neurons rescued the spine and synapse deficits in the cortical neurons while knockdown of NRXN3 204 in healthy neurons phenocopied spine and synapse deficits seen in schizophrenia cortical neurons. The antipsychotic clozapine increased expression of the NRXN3 204 isoform in schizophrenia cortical neurons and rescued the spine and synapse density deficits.
conclusionsTaken together, our findings in iPSC-derived cortical neurons recapitulate cell type-specific findings in postmortem studies in schizophrenia and have led to the identification of a specific isoform of NRXN3 that modulates synaptic deficits in schizophrenia neurons.
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