Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia

Gracias, Jessica; Orhan, Funda; Hörbeck, Elin; Holmén-Larsson, Jessica; Khanlarkani, Neda; Malwade, Susmita; Goparaju, Sravan K.; Schwieler, Lilly; Demirel, İlknur Ş.; Fu, Ting; Fatourus-Bergman, Helena; Pelanis, Aurimantas; Goold, Carleton P.; Goulding, Anneli; Annerbrink, Kristina; Isgren, Anniella; Sparding, Timea; Schalling, Martin; Yañez, Viviana A. Carcamo; Göpfert, Jens; Nilsson, Johanna; Westman‐Brinkmalm, Ann; Blennow, Kaj; Zetterberg, Henrik; Engberg, Göran; Piehl, Fredrik; Sheridan, Steven D.; Perlis, Roy H.; Červenka, Simon; Erhardt, Sophie; Landén, Mikael; Sellgren, Carl M.

doi:10.1038/s41467-022-33797-6

Cited by 13 publications

(9 citation statements)

References 37 publications

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“…We have highlighted a potential role of C4, and this is now supported by recent evidence that cerebrospinal fluid concentrations of C4A are elevated in two separate cohorts of people with schizophrenia, and inversely related to levels of a synaptic marker [171]. However, it is important to recognise that this is only one potential pathway and other immune pathways or alternative mechanisms may also be involved.…”

Section: Gaps In the Evidence And Future Directionsmentioning

confidence: 66%

The synaptic hypothesis of schizophrenia version III: a master mechanism

Howes

Onwordi

2023

Mol Psychiatry

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The synaptic hypothesis of schizophrenia has been highly influential. However, new approaches mean there has been a step-change in the evidence available, and some tenets of earlier versions are not supported by recent findings. Here, we review normal synaptic development and evidence from structural and functional imaging and post-mortem studies that this is abnormal in people at risk and with schizophrenia. We then consider the mechanism that could underlie synaptic changes and update the hypothesis. Genome-wide association studies have identified a number of schizophrenia risk variants converging on pathways regulating synaptic elimination, formation and plasticity, including complement factors and microglial-mediated synaptic pruning. Induced pluripotent stem cell studies have demonstrated that patient-derived neurons show pre- and post-synaptic deficits, synaptic signalling alterations, and elevated, complement-dependent elimination of synaptic structures compared to control-derived lines. Preclinical data show that environmental risk factors linked to schizophrenia, such as stress and immune activation, can lead to synapse loss. Longitudinal MRI studies in patients, including in the prodrome, show divergent trajectories in grey matter volume and cortical thickness compared to controls, and PET imaging shows in vivo evidence for lower synaptic density in patients with schizophrenia. Based on this evidence, we propose version III of the synaptic hypothesis. This is a multi-hit model, whereby genetic and/or environmental risk factors render synapses vulnerable to excessive glia-mediated elimination triggered by stress during later neurodevelopment. We propose the loss of synapses disrupts pyramidal neuron function in the cortex to contribute to negative and cognitive symptoms and disinhibits projections to mesostriatal regions to contribute to dopamine overactivity and psychosis. It accounts for the typical onset of schizophrenia in adolescence/early adulthood, its major risk factors, and symptoms, and identifies potential synaptic, microglial and immune targets for treatment.

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Section: Gaps In the Evidence And Future Directionsmentioning

confidence: 66%

The synaptic hypothesis of schizophrenia version III: a master mechanism

Howes

Onwordi

2023

Mol Psychiatry

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“…For example, C4A genomic diversity and inferred C4 expression do not always equate with a risk of schizophrenia independently of the immune-gene rich major histocompatibility complex region or outside of European and African populations [55, 99, 100]. Furthermore, a role for synaptic pruning mechanisms attributable to C4 is predominantly based on experiments performed in rodent models, whose single C4 gene is not structurally homologous to the two-gene human C4 system [28, 34, 101] but see [52, 102]. C4A expression in the human brain was in part based on work that may have included diagnostically heterogeneous control groups.…”

Section: Discussionmentioning

confidence: 99%

“…Recent evidence, for example, supports a complement and coagulation protein pathway mechanism by which omega-3 polyunsaturated fatty acids might contribute to cognitive and symptom improvements in individuals with early psychosis [41]. A role for C4 in neuroinflammation is based on positive, negative, and mixed associations of C4 levels with markers of white matter integrity, CSF biochemistry, cortical thinning, and patterns of expression with postmortem brain structures and functions [31,32,42,51,52,54,[90][91][92][93][94][95][96][97].…”

Section: Discussionmentioning

confidence: 99%

“…For example, CSF C4, but not plasma C4, was increased in individuals with schizophrenia compared to controls, and this group difference was only detectable when comparisons were corrected for age and sex [51]. Investigators found C4A elevations in CSF from first episode psychosis patients who developed schizophrenia (FEP-SCZ) compared to healthy control group levels and levels from FEP patients who did not develop schizophrenia [52]. C4B levels in CSF were not different between groups, as expected if the C4A locus is driving the C4 genetic association in schizophrenia.…”

Section: Introductionmentioning

confidence: 99%

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Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Severance,

Prandovszky,

Yang

et al. 2023

Dev Neurosci

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Complex brain disorders like schizophrenia may have multifactorial origins related to mis-timed heritable and environmental factors interacting during neurodevelopment. Infections, inflammation, and autoimmune diseases are over-represented in schizophrenia leading to immune system-centered hypotheses. Complement component C4 is genetically and neurobiologically associated with schizophrenia, and its dual activity peripherally and in the brain makes it an exceptional target for biomarker development. Studies to evaluate the biomarker potential of plasma or serum C4 in schizophrenia do so to understand how peripheral C4 might reflect central nervous system (CNS)-derived neuroinflammation, synapse pruning and other mechanisms. This effort, however, has produced mostly conflicting results, with peripheral C4 sometimes elevated, reduced or unchanged between comparison groups. We undertook a pilot biomarker development study to systematically identify sociodemographic, genetic, and immune-related variables (autoimmune, infection-related, gastrointestinal (GI), inflammatory), which may be associated with plasma C4 levels in schizophrenia (SCH; n=335) and/or in non-psychiatric comparison subjects (NCs; n=233). As with previously inconclusive studies, we detected no differences in plasma C4 levels between SCH and NCs. In contrast, levels of general inflammation, C-Reactive Protein (CRP), were significantly elevated in SCH compared to NCs (ANOVA, F=20.74, p<0.0001), suggestive that plasma C4 and CRP may reflect different sources or causes of inflammation. In multivariate regressions of C4 gene copy number variants (CNVs), plasma C4 levels were correlated only for C4A (not C4B, C4L, C4S) and only in NCs (R Coeff=0.39, CI=0.01-0.77, R2=0.18, p<0.01; not SCH). Other variables associated with plasma C4 levels only in NCs included sex, double-stranded DNA (dsDNA) IgG, tissue-transglutaminase (TTG) IgG, and cytomegalovirus (CMV) IgG. Toxoplasma gondii IgG was the only variable significantly correlated with plasma C4 in SCH but not in NCs. Many variables were associated with plasma C4 in both groups (body mass index (BMI), race, CRP, N-methyl-D-aspartate receptor (NMDAR) NR2 subunit IgG, TTG IgA, lipopolysaccharide (LPS)-binding protein (LBP), and soluble CD14 (sCD14). While the direction of most C4 associations was positive, autoimmune markers tended to be inverse, and associated with reduced plasma C4 levels. When NMDAR NR2 autoantibody-positive individuals were removed, plasma C4 was elevated in SCH versus NCs (ANOVA, F=5.16, p<0.02). Our study was exploratory and confirmation of the many variables associated with peripheral C4 require replication. Our preliminary results point toward autoimmune factors and exposure to the pathogen, T. gondii, as possibly significant contributors to variability of total C4 protein levels in plasma of individuals with schizophrenia.

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“…45,46 The discovery that KYNA promotes microglia-mediated synaptic pruning then defines a precise and plausible molecular mechanism linking elevated KYNA levels to the observed cognitive deficits in patients with SCZ. It is important to note that a C4A induced sensitization of the microglial synapse recognition system in SCZ to some extent overlaps with this activity-driven mechanism mediated by KYNA as interleukin (IL)-1β elevated in SCZ 47 both stimulates the expression of C4A 48 and the production of KYNA (by inducing expression of tryptophan-2,3-dioxygenase upstream of the KATs). 49 In line with an integrated mechanism, C4A negative co-expression networks, as the KAT-positive networks, also enrich for synaptic pathways that involve SCZ risk variants.…”

Section: Discussionmentioning

confidence: 99%

Kynurenic acid promotes activity-dependent synaptic pruning in schizophrenia

Orhan,

Malwade,

Khanlarkhani

et al. 2023

Preprint

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Schizophrenia is a neurodevelopmental disorder characterized by an excessive loss of synapses. Recent data suggest that this is due to increased microglia-mediated synaptic pruning. Here, we utilize human induced pluripotent stem cell-derived models to show that kynurenic acid (KYNA), an endogenous NMDA-receptor antagonist observed to be increased in the brains of individuals with schizophrenia, reduces neuronal activity and promote microglial uptake of synapses. In a human brain organoid model, we confirm reduced microglia-mediated synaptic pruning upon inhibiting the endogenous KYNA production. To verify our experimental data in a clinical context, we integrate large-scale transcriptomic and genetic datasets and show that KYNA-producing kynurenine aminotransferases (KATs) enrich for genes governing synaptic activity and genetic risk variants for schizophrenia. Together, these results link genetic risk variants for schizophrenia to elevated production of KYNA and excessive activity-dependent synaptic pruning, while implicating pharmacological inhibition of KATs as a strategy to avoid synapse loss in schizophrenia.

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Cerebrospinal fluid concentration of complement component 4A is increased in first episode schizophrenia

Cited by 13 publications

References 37 publications

The synaptic hypothesis of schizophrenia version III: a master mechanism

The synaptic hypothesis of schizophrenia version III: a master mechanism

Prospects and Pitfalls of Plasma Complement C4 in Schizophrenia: Building a Better Biomarker

Kynurenic acid promotes activity-dependent synaptic pruning in schizophrenia

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