ArticleMolecular psychiatry2021
Elevated expression of complement C4 in the mouse prefrontal cortex causes schizophrenia-associated phenotypes.
Article in Molecular psychiatry, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.
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Who cites it
32 citing papers in PubMed, 58 citations in OpenAlex.
- Sparse neuronal C4 elevation induces network-wide transcriptomic and lipid-droplet remodeling in the cortical microenvironment.PLoS computational biology · 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
- A vicious cycle of microglial dysfunction: bridging synaptic pruning and neuroinflammation across the neurodevelopmental continuum.Frontiers in immunology · 2026Review
- A spatial atlas of the complement system uncovers unique expression patterns in postnatal brain development in mice.Nature communications · 2025Article
- Impact of rs2046045 SNP in PDE8B on TSH Levels: Insights into Genetic Susceptibility to Hypothyroidism.Biochemical genetics · 2025Article
- Microdosing Psychedelics to Restore Synaptic Density in Schizophrenia.International journal of molecular sciences · 2025Review
- GADD45G operates as a pathological sensor orchestrating reactive gliosis and neurodegeneration.Neuron · 2025Article
- Increased Complement C4 in a Sparse Neuronal Subset Induces Network-Wide Transcriptomic Alterations in the Prefrontal Cortex.bioRxiv : the preprint server for biology · 2025Article
- Article
- Perturbed cell fate decision by schizophrenia-associated AS3MTScience advances · 2025Article
- The schizophrenia risk gene C4 induces pathological synaptic loss by impairing AMPAR trafficking.Molecular psychiatry · 2025Article
- Influence of antipsychotic drugs on microglia-mediated neuroinflammation in schizophrenia: perspectives in an astrocyte-microglia co-culture model.Frontiers in psychiatry · 2025Review
- The role of prefrontal-hippocampal functional connectivity in schizophrenia-related cognitive dysfunction and the thalamic ventral midline involvement:Frontiers in neuroscience · 2025Review
- Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.iScience · 2024Article
- Synaptic pruning in schizophrenia is not classical.Brain, behavior, and immunity · 2024Article
- Altered Rbfox1-Vamp1 pathway and prefrontal cortical dysfunction in schizophrenia.Molecular psychiatry · 2024Article
- Overexpression of the schizophrenia risk gene C4 in PV cells drives sex-dependent behavioral deficits and circuit dysfunction.bioRxiv : the preprint server for biology · 2024Article
- Association study of the complement component C4 gene and suicide risk in schizophrenia.Schizophrenia (Heidelberg, Germany) · 2024Article
- Reorganization of adolescent prefrontal cortex circuitry is required for mouse cognitive maturation.Neuron · 2024Article
- Mast cell stabilizer, an anti-allergic drug, reduces ventricular arrhythmia risk via modulation of neuroimmune interaction.Basic research in cardiology · 2024Article
Corrections and comments
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Authors and funding
12 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Accumulating evidence supports immune involvement in the pathogenesis of schizophrenia, a severe psychiatric disorder. In particular, high expression variants of C4, a gene of the innate immune complement system, were shown to confer susceptibility to schizophrenia. However, how elevated C4 expression may impact brain circuits remains largely unknown. We used in utero electroporation to overexpress C4 in the mouse prefrontal cortex. We found reduced glutamatergic input to pyramidal cells of juvenile and adult, but not of newborn C4-overexpressing (C4-OE) mice, together with decreased spine density, which mirrors spine loss observed in the schizophrenic cortex. Using time-lapse two-photon imaging in vivo, we observed that these deficits were associated with decreased dendritic spine gain and elimination in juvenile C4-OE mice, which may reflect poor formation and/or stabilization of immature spines. In juvenile and adult C4-OE mice, we found evidence for NMDA receptor hypofunction, another schizophrenia-associated phenotype, and synaptic accumulation of calcium-permeable AMPA receptors. Alterations in cortical GABAergic networks have been repeatedly associated with schizophrenia. We found that functional GABAergic transmission was reduced in C4-OE mice, in line with diminished GABA release probability from parvalbumin interneurons, lower GAD67 expression, and decreased intrinsic excitability in parvalbumin interneurons. These cellular abnormalities were associated with working memory impairment. Our results substantiate the causal relationship between an immunogenetic risk factor and several distinct cortical endophenotypes of schizophrenia and shed light on the underlying cellular mechanisms.
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