Neuroimmune cortical organoids overexpressing C4A exhibit multiple schizophrenia endophenotypes
Morgan M. StantoniD, Sara Modan, Patrick M. Taylor, Harsh N. HarianiiD, Jordan M. SorokiniD, Brian G. RashiD, Sneha B. RaoiD, Alejandro ToboniD, Luigi Enriquez, Brenda Dang, Dorah Owango, Shannon K. O’Neill, Carlos Castrillo, Justin Nicola, Kathy Ye, Robert M. Blattner, Federico GonzãleziD, Dexter D. AntonioiD, Pavan RamkumariD, Andy Lash, Douglas Flanzer, Sophia BardehleiD, Stefka GyonevaiD, Kevan D. ShahiD, Saul KatoiD, Gaia Skibinski
Abstract
Elevated expression of the complement component 4A (C4A) protein has been linked to an increased risk of schizophrenia (SCZ). However, there are few human models available to study the mechanisms by which C4A contributes to the development of SCZ. In this study, we established a C4A overexpressing neuroimmune cortical organoid (NICO) model, which includes mature neuronal cells, astrocytes, and functional microglia. The C4A NICO model recapitulated several neuroimmune endophenotypes observed in SCZ patients, including modulation of inflammatory genes and increased cytokine secretion. C4A expression also increased microglia-mediated synaptic uptake in the NICO model, supporting the hypothesis that synapse and brain volume loss in SCZ patients may be due to excessive microglial pruning. Our results highlight the role of C4A in the immunogenetic risk factors for SCZ and provide a human model for phenotypic discovery and validation of immunomodulating therapies.
02 /Specification & Classification
Click any tag to browse matching papers- Citations
- 2
- Organism
- Research Focus
- Approach
Reproducibility ledger
Nobody has reported trying to reproduce this paper yet. Did you replicate an experiment or run the code? Your report saves the next lab a week.
Sign in to file a reproducibility report.
Related papers
- Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes
Mélanie Druart, Marika Nosten‐Bertrand, … Corentin Le Magueresse·Molecular PsychiatryPeer-reviewed·Apr 9, 2021
- Increased expression of schizophrenia-associated gene C4 leads to hypoconnectivity of prefrontal cortex and reduced social interaction
Ashley L. Comer, Tushare Jinadasa, … Alberto Cruz‐Martín·PLoS BiologyPeer-reviewed·Jan 14, 2020
- Sparse Neuronal C4 Elevation Induces Network-Wide Transcriptomic and Lipid-Droplet Remodeling in the Cortical Microenvironment
Marta Sánchez-Carbonell, Sonia Bolshakova, … Alberto Cruz‐Martín·bioRxiv·May 29, 2025
- Peripheral Complement C4 Protein in Schizophrenia: Association with Gene Copy Number and Immune Cell Subtypes
Agnieszka Kalinowski, Claudia Macaubas, … Alexander Eckehart Urban·Proceedings of the National Academy of SciencesPeer-reviewed·May 11, 2026
- CUB and Sushi Multiple Domains 1 (CSMD1) opposes the complement cascade in neural tissues
Matthew L. Baum, Daniel K. Wilton, … Beth Stevens·Brain Behavior and ImmunityPeer-reviewed·Mar 27, 2024
- Increased microglial synapse elimination in patient-specific models of schizophrenia
Carl M. Sellgren, Jessica Gracias, … Roy H. Perlis·bioRxiv·Dec 8, 2017