ArticleBiological psychiatry2023
Excitatory Dysfunction Drives Network and Calcium Handling Deficits in 16p11.2 Duplication Schizophrenia Induced Pluripotent Stem Cell-Derived Neurons.
Article in Biological psychiatry, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers, 1 of them a synthesis that pooled it.
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17 citing papers in PubMed, 1 synthesis or guideline pooled it, 26 citations in OpenAlex.
- Neural excitation/inhibition imbalance and neurodevelopmental pathology in human copy number variant syndromes: a systematic review.Journal of neurodevelopmental disorders · 2025Pooled it
- Developmentally dynamic, non-convergent transcriptomic profiles in CNV models for schizophrenia risk.Molecular psychiatry · 2026Article
- Systems-Level Transcriptomic and Cellular Architecture of the Human Striatum in Schizophrenia and Bipolar Psychosis.Biology · 2026Article
- Review
- Histone H1 variants regulate neurodevelopmental transcriptional programs in autism with 16p11.2 deletion.Genome biology · 2026Article
- Loss of function of the chromatin remodeling geneProceedings of the National Academy of Sciences of the United States of America · 2026Article
- How copy number variations shape brain developmental disorders: Unraveling the synaptic puzzle.Psychiatry and clinical neurosciences · 2026Review
- Cell-type specific global reprogramming of the transcriptome and epigenome in induced neurons with the 16p11.2 neuropsychiatric CNVs.European journal of human genetics : EJHG · 2025Article
- Schizophrenia genomics: genetic complexity and functional insights.Nature reviews. Neuroscience · 2024Review
- Astrocytes Regulate Neuronal Network Burst Frequency Through NMDA Receptors in a Species- and Donor-Specific Manner.Biological psychiatry global open science · 2024Article
- Precision medicine for psychotic disorders: objective assessment, risk prediction, and pharmacogenomics.Molecular psychiatry · 2024Article
- iPSC-derived models of PACS1 syndrome reveal transcriptional and functional deficits in neuron activity.Nature communications · 2024Article
- Harnessing the potential of human induced pluripotent stem cells, functional assays and machine learning for neurodevelopmental disorders.Frontiers in neuroscience · 2024Review
- Understanding copy number variations through their genes: a molecular view on 16p11.2 deletion and duplication syndromes.Frontiers in pharmacology · 2024Review
- Article
- A robust and reliable methodology to perform GECI-based multi-time point neuronal calcium imaging within mixed cultures of human iPSC-derived cortical neurons.Frontiers in neuroscience · 2023Article
- Brain Lipids and Lipid Droplet Dysregulation in Alzheimer's Disease and Neuropsychiatric Disorders.Complex psychiatryReview
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19 authors at 3 institutions in 1 country.
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Abstract
backgroundSchizophrenia (SCZ) is a debilitating psychiatric disorder with a large genetic contribution; however, its neurodevelopmental substrates remain largely unknown. Modeling pathogenic processes in SCZ using human induced pluripotent stem cell-derived neurons (iNs) has emerged as a promising strategy. Copy number variants confer high genetic risk for SCZ, with duplication of the 16p11.2 locus increasing the risk 14.5-fold.
methodsTo dissect the contribution of induced excitatory neurons (iENs) versus GABAergic (gamma-aminobutyric acidergic) neurons (iGNs) to SCZ pathophysiology, we induced iNs from CRISPR (clustered regularly interspaced short palindromic repeats)-Cas9 isogenic and SCZ patient-derived induced pluripotent stem cells and analyzed SCZ-related phenotypes in iEN monocultures and iEN/iGN cocultures.
resultsIn iEN/iGN cocultures, neuronal firing and synchrony were reduced at later, but not earlier, stages of in vitro development. These were fully recapitulated in iEN monocultures, indicating a primary role for iENs. Moreover, isogenic iENs showed reduced dendrite length and deficits in calcium handling. iENs from 16p11.2 duplication-carrying patients with SCZ displayed overlapping deficits in network synchrony, dendrite outgrowth, and calcium handling. Transcriptomic analysis of both iEN cohorts revealed molecular markers of disease related to the glutamatergic synapse, neuroarchitecture, and calcium regulation.
conclusionsOur results indicate the presence of 16p11.2 duplication-dependent alterations in SCZ patient-derived iENs. Transcriptomics and cellular phenotyping reveal overlap between isogenic and patient-derived iENs, suggesting a central role of glutamatergic, morphological, and calcium dysregulation in 16p11.2 duplication-mediated pathogenesis. Moreover, excitatory dysfunction during early neurodevelopment is implicated as the basis of SCZ pathogenesis in 16p11.2 duplication carriers. Our results support network synchrony and calcium handling as outcomes directly linked to this genetic risk variant.
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