ArticleNature neuroscience2021
Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice.
Article in Nature neuroscience, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 185 papers, 1 of them a synthesis that pooled it.
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185 citing papers in PubMed, 1 synthesis or guideline pooled it, 315 citations in OpenAlex.
- Inflammatory cytokine alterations in genetic and clinical high risk groups of psychosis: a systematic review and network meta-analysis.Psychological medicine · 2026Pooled it
- Estimating protein isoform abundances with [Formula: see text].Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mismatch negativity matures in adolescence and without sensitivity to microglial depletion.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Complement component C4 regulates amyloid pathology and glial reactivity in mouse model of Alzheimer's Disease.bioRxiv : the preprint server for biology · 2026Article
- Review
- Microglia and neuroinflammation: An in-depth analysis from functional diversity to disease mechanisms.Clinical and translational medicine · 2026Review
- Retinal Origins of Aberrant Salience in Schizophrenia: The Perceptual Theory.Biological psychiatry global open science · 2026Review
- Article
- Schizophrenia: from mechanism to therapy.Science China. Life sciences · 2026Review
- Convergence of schizophrenia risk genes on CALN1 disrupts human forebrain development and drives core psychotic behaviors including hallucination-like perception.BMC medicine · 2026Article
- The Molecular Machinery of Synaptic Plasticity and Its Potential Role in the Aetiology of Schizophrenia.Molecular neurobiology · 2026Review
- Microglia and neuroinflammation: function, heterogeneity, and crosstalk.Cellular & molecular immunology · 2026Review
- Peripheral complement C4 protein in schizophrenia: Association with gene copy number and immune cell subtypes.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Whole brain grey matter synaptic terminal density, age and intellectual functioning in schizophrenia: an in vivo [Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2026Article
- Divergence of C4A and C4B in first-episode psychosis: Insights from CSF and plasma immune profiling.Translational psychiatry · 2026Article
- Dysregulation of the BRD2-FGF17 Signal Pathway Induces Abnormal Forebrain Development Associated with Schizophrenia.Neuroscience bulletin · 2026Article
- Novel drug treatments for schizophrenia.Nature reviews. Drug discovery · 2026Review
- The Effects of Gut Microbiota, Plasma Metabolites, Immune Cells, Blood Cells and Cytokines on Schizophrenia: A Bidirectional Two-Sample Mendelian Randomisation Study.Actas espanolas de psiquiatria · 2026Article
- Schizophrenia-Related Synaptic Dysfunction and Abnormal Sensorimotor Gating in Akap11-Deficient Mice.Schizophrenia bulletin · 2026Article
- B cell pathways implicate shared genetic architecture between schizophrenia and immune-mediated diseases.Journal of translational medicine · 2026Article
125 more citing papers are in PubMed but not listed here.
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9 authors at 2 institutions in 1 country.
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Abstract
The complement component 4 (C4) gene is linked to schizophrenia and synaptic refinement. In humans, greater expression of C4A in the brain is associated with an increased risk of schizophrenia. To investigate this genetic finding and address how C4A shapes brain circuits in vivo, here, we generated a mouse model with primate-lineage-specific isoforms of C4, human C4A and/or C4B. Human C4A bound synapses more efficiently than C4B. C4A (but not C4B) rescued the visual system synaptic refinement deficits of C4 knockout mice. Intriguingly, mice without C4 had normal numbers of cortical synapses, which suggests that complement is not required for normal developmental synaptic pruning. However, overexpressing C4A in mice reduced cortical synapse density, increased microglial engulfment of synapses and altered mouse behavior. These results suggest that increased C4A-mediated synaptic elimination results in abnormal brain circuits and behavior. Understanding pathological overpruning mechanisms has important therapeutic implications in disease conditions such as schizophrenia.
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