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Peer-reviewedCC BYPLOS Computational Biology

Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment

  • Marta Sánchez-Carbonell1,2
  • Sonia Bolshakova3,4
  • Juan E Ávila-Pagán1,2,5
  • Yaseer A Sabir1,2,6
  • Clay Griffin-Derr7,8
  • Dominik G Stich2,9
  • Sofia V Cieslewicz1,2,10
  • Sheyla Esther Carmen Sifuentes11
  • Rhushikesh A Phadke12,13
  • Alison Brack12,13
  • Anna Hasche-Kluender14
  • Paige Caley1,2
2 more authors
  • Caroline Dias15
  • Alberto Cruz-Martín1,2,5,12,13,14
15 affiliations
  1. 1Department of Anesthesiology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
  2. 2NeuroTechnology Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
  3. 3Bioinformatics MS Program, Boston University, Boston, Massachusetts, United States of America.
  4. 4Stanley Center for Psychiatric Research at the Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.
  5. 5Human Medical Genetics and Genomics Graduate Program (HMGGP), University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
  6. 6Department of Computer Science and Engineering, University of Colorado Denver, Denver, Colorado, United States of America.
  7. 7Data Science and Machine Learning Program, Department of Computer Sciences, Metropolitan State University of Denver, Denver, Colorado, United States of America.
  8. 8Genomics Research Experiences for Undergraduates (GREU) Program, Center for Advanced STEM Education (CASE), Metropolitan State University of Denver, Denver, Colorado, United States of America.
  9. 9Advanced Light Microscopy Core, NeuroTechnology Center, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
  10. 10Quantitative Biosciences and Engineering, Colorado School of Mines, Golden, Colorado, United States of America.
  11. 11Escuela de Genética y Biotecnología, Universidad Nacional Mayor de San Marcos, Lima, Peru.
  12. 12Molecular Biology, Cell Biology and Biochemistry Program, Boston University, Boston, Massachusetts, United States of America.
  13. 13Neurobiology Section in the Department of Biology, Boston University, Boston, Massachusetts, United States of America.
  14. 14Medical Scientist Training Program, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
  15. 15Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States of America.
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Abstract

The complement component C4 regulates synaptic refinement and plasticity in the brain and has been implicated in multiple neurological and psychiatric disorders, with especially strong genetic evidence linking elevated C4A expression to schizophrenia. However, it remains unclear whether localized C4 elevation in a small neuronal population is sufficient to reshape broader cortical gene-regulatory programs and cellular phenotypes. To address this question, we overexpressed mouse C4 in approximately 2% of prefrontal cortical neurons using in utero electroporation and performed bulk RNA sequencing on microdissected prefrontal cortex. Despite the sparse manipulation, C4-OE was associated with broad transcriptional remodeling across tissue composed predominantly of untransfected cells, including coordinated changes in cholesterol biosynthesis, axon- and synaptic-associated programs, vascular/ECM pathways, and immune- and stress-related responses. Comparison with a schizophrenia synaptic proteomic dataset identified limited global correspondence but selective gene- and pathway-level overlap in specific molecular programs. Reference-based projection of directional DEG signatures onto a cortical single-cell transcriptomic reference further identified cell-type-associated structure, including prominent astrocyte- and vascular-associated axes and distinct lipid/metabolic, vascular/endothelial–interferon-associated, and immune/stress correlation domains. Spatial validation with MFISH showed increased Hmgcr expression in neighboring GFP-negative cells, while PLIN2 imaging revealed increased DAPI-associated/perinuclear lipid-droplet burden within the local C4-OE field. Together, these findings support a model in which sparse neuronal C4 elevation is associated with broader remodeling of the local cortical environment, including a non-cell-autonomous component involving neighboring-cell lipid-associated responses. These results expand the interpretation of C4 risk biology beyond synapse elimination alone and suggest that focal immune-gene dysregulation can engage lipid-homeostatic, stress-related, and cell-type-associated transcriptional programs relevant to cortical circuit vulnerability. Author summary: Complement component C4 is best known for its role in immune defense, but increasing evidence suggests that altered C4 levels can also influence brain development and disease-relevant neural circuits. Here, we asked what happens when C4 is increased in only a sparse subset of cortical neurons. Using a mouse model with C4 elevation in a small population of prefrontal cortical neurons, we found that this localized perturbation was associated with broad molecular changes across the surrounding cortical field. Transcriptomic analyses revealed coordinated changes in cholesterol biosynthesis and lipid metabolism, synaptic and neuronal programs, vascular-associated pathways, and immune- and stress-related responses. Spatial validation further showed increased Hmgcr expression and greater PLIN2-positive lipid-droplet burden in neighboring GFP-negative cells, supporting a non-cell-autonomous component of the response. These findings show that a highly localized increase in one immune-linked gene can ripple across the surrounding cortex, reshaping lipid homeostasis and microenvironmental states linked to circuit vulnerability.

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Cite

BibTeXRIS
BibTeX
@article{sanchezcarbonell2026sparse,
  title = {{Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment}},
  author = {Marta Sánchez-Carbonell and Sonia Bolshakova and Juan E Ávila-Pagán and Yaseer A Sabir and Clay Griffin-Derr and Dominik G Stich and Sofia V Cieslewicz and Sheyla Esther Carmen Sifuentes and Rhushikesh A Phadke and Alison Brack and Anna Hasche-Kluender and Paige Caley and Caroline Dias and Alberto Cruz-Martín},
  journal = {PLOS Computational Biology},
  year = {2026},
  month = oct,
  doi = {10.1371/journal.pcbi.1014871},
  url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014871},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment
AU  - Marta Sánchez-Carbonell
AU  - Sonia Bolshakova
AU  - Juan E Ávila-Pagán
AU  - Yaseer A Sabir
AU  - Clay Griffin-Derr
AU  - Dominik G Stich
AU  - Sofia V Cieslewicz
AU  - Sheyla Esther Carmen Sifuentes
AU  - Rhushikesh A Phadke
AU  - Alison Brack
AU  - Anna Hasche-Kluender
AU  - Paige Caley
AU  - Caroline Dias
AU  - Alberto Cruz-Martín
PY  - 2026
DA  - 2026/10/12
JO  - PLOS Computational Biology
DO  - 10.1371/journal.pcbi.1014871
UR  - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014871
AB  - The complement component C4 regulates synaptic refinement and plasticity in the brain and has been implicated in multiple neurological and psychiatric disorders, with especially strong genetic evidence linking elevated C4A expression to schizophrenia. However, it remains unclear whether localized C4 elevation in a small neuronal population is sufficient to reshape broader cortical gene-regulatory programs and cellular phenotypes. To address this question, we overexpressed mouse C4 in approximately 2% of prefrontal cortical neurons using in utero electroporation and performed bulk RNA sequencing on microdissected prefrontal cortex. Despite the sparse manipulation, C4-OE was associated with broad transcriptional remodeling across tissue composed predominantly of untransfected cells, including coordinated changes in cholesterol biosynthesis, axon- and synaptic-associated programs, vascular/ECM pathways, and immune- and stress-related responses. Comparison with a schizophrenia synaptic proteomic dataset identified limited global correspondence but selective gene- and pathway-level overlap in specific molecular programs. Reference-based projection of directional DEG signatures onto a cortical single-cell transcriptomic reference further identified cell-type-associated structure, including prominent astrocyte- and vascular-associated axes and distinct lipid/metabolic, vascular/endothelial–interferon-associated, and immune/stress correlation domains. Spatial validation with MFISH showed increased Hmgcr expression in neighboring GFP-negative cells, while PLIN2 imaging revealed increased DAPI-associated/perinuclear lipid-droplet burden within the local C4-OE field. Together, these findings support a model in which sparse neuronal C4 elevation is associated with broader remodeling of the local cortical environment, including a non-cell-autonomous component involving neighboring-cell lipid-associated responses. These results expand the interpretation of C4 risk biology beyond synapse elimination alone and suggest that focal immune-gene dysregulation can engage lipid-homeostatic, stress-related, and cell-type-associated transcriptional programs relevant to cortical circuit vulnerability. Author summary: Complement component C4 is best known for its role in immune defense, but increasing evidence suggests that altered C4 levels can also influence brain development and disease-relevant neural circuits. Here, we asked what happens when C4 is increased in only a sparse subset of cortical neurons. Using a mouse model with C4 elevation in a small population of prefrontal cortical neurons, we found that this localized perturbation was associated with broad molecular changes across the surrounding cortical field. Transcriptomic analyses revealed coordinated changes in cholesterol biosynthesis and lipid metabolism, synaptic and neuronal programs, vascular-associated pathways, and immune- and stress-related responses. Spatial validation further showed increased Hmgcr expression and greater PLIN2-positive lipid-droplet burden in neighboring GFP-negative cells, supporting a non-cell-autonomous component of the response. These findings show that a highly localized increase in one immune-linked gene can ripple across the surrounding cortex, reshaping lipid homeostasis and microenvironmental states linked to circuit vulnerability.
SN  - 1553-7358
SN  - 1553-734X
ER  -