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Increased Complement C4 in a Sparse Neuronal Subset Induces Network-Wide Transcriptomic Alterations in the Prefrontal
Sonia Bolshakova1,2, Sheyla Esther Carmen Sifuentes3, Rhushikesh A Phadke4,5
1Bioinformatics MS Program, Boston University, Boston, MA, United States.
Biorxiv : the Preprint Server for Biology
|June 12, 2025
Summary
Sparse complement C4 gene overexpression in mouse neurons triggered widespread brain network changes. This suggests local complement dysregulation can disrupt neural circuits, potentially contributing to neurological disorders like schizophrenia.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- The complement (C) pathway is crucial for immunity but its dysregulation can cause tissue injury.
- In the brain, complement proteins influence synaptic plasticity, and their dysregulation is linked to neurological disorders.
- The impact of localized complement upregulation on broader cortical networks is not well understood.
Purpose of the Study:
- To investigate how localized complement C4 gene overexpression affects neural circuits.
- To explore the potential mechanisms by which complement dysregulation may disrupt brain function.
- To assess the relevance of mouse models to human neurological and psychiatric disorders.
Main Methods:
- Overexpression of the schizophrenia (SCZ) risk gene C4 in a small subset of mouse prefrontal cortex neurons using in utero electroporation.
- Bulk RNA sequencing of microdissected brain tissue to analyze transcriptional changes.
- Co-expression analysis to identify gene modules and network alterations.
- Comparison of mouse gene signatures with human SCZ proteomic datasets.
Main Results:
- Sparse C4 overexpression induced widespread transcriptional changes in predominantly untransfected cells.
- Upregulated genes were involved in cholesterol biosynthesis, axon guidance, synaptic plasticity, cytoprotection, and neurogenesis.
- A C4b-containing module indicated altered dendritic development and cell cycle regulation.
- Immune and inflammatory genes were downregulated, suggesting homeostatic suppression.
- Conserved gene signatures were found between the mouse model and human SCZ datasets.
Conclusions:
- Localized C4 overexpression can trigger extensive transcriptional alterations across neural networks.
- Sparse complement dysregulation may propagate through cortical networks, leading to broader functional disruption.
- This model captures disease-relevant mechanisms and highlights the role of complement in neurological conditions.
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