Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice

Yilmaz, Melis; Yalçın, Esra; Présumey, Jessy; Aw, Ernest; Ma, Minghe; Whelan, Christopher W.; Stevens, Beth; McCarroll, Steven A.; Carroll, Michael

doi:10.1038/s41593-020-00763-8

Cited by 216 publications

(162 citation statements)

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“…However, so far a role for complement signaling in synaptic or axonal pruning outside of the retino-thalamic system lacks strong evidence (29)(30)(31). Here we show that cortical structures in mice lacking C3r undergo apparently normal adolescent synaptic pruning and perinatal axonal pruning.…”

Section: Introductionmentioning

confidence: 53%

“…Based on the demonstrated role of complement signaling in the retino-thalamic system in mice (17,32) the hypothesis was put forward that complement signaling could have a role in neuronal pruning more generally. Several recent studies have found that overexpression of C4 in the developing mouse cortex impacts spine density and function (31,64). However, loss of function mutations in the mouse C4 gene did not show a phenotype in these studies (31), leaving open the question of whether complement mediates cortical pruning in the undisturbed animal.…”

Section: Discussionmentioning

confidence: 95%

“…Several recent studies have found that overexpression of C4 in the developing mouse cortex impacts spine density and function (31,64). However, loss of function mutations in the mouse C4 gene did not show a phenotype in these studies (31), leaving open the question of whether complement mediates cortical pruning in the undisturbed animal. Here we confirmed that mice lacking the microglia complement receptor C3r do not show alterations in synaptic or axonal pruning, but instead show deficits in the elimination of apoptotic neurons, and that this has a long-term impact on brain functional connectivity in a manner that selectively affects Schizophrenia-associated brain regions.…”

Section: Discussionmentioning

confidence: 95%

“…However, it remained unclear whether complement had a role in synaptic pruning outside of the retino-thalamic system. This question gained increased importance with the discovery that common copy number variants in complement factor C4 showed a dose-dependent association with risk for schizophrenia in human populations (31,62,63). Based on the demonstrated role of complement signaling in the retino-thalamic system in mice (17,32) the hypothesis was put forward that complement signaling could have a role in neuronal pruning more generally.…”

Section: Discussionmentioning

confidence: 99%

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Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

Deivasigamani

Miteva

Natale

et al. 2021

Preprint

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Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we show that mice lacking the complement 3 receptor (C3r), the major microglia complement receptor, fail to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking C3r show a deficit in the perinatal elimination of neurons, both in the retina as well as in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a preferential role for complement in promoting neuronal elimination in the developing brain and argue for a reconsideration of the role of complement in synaptic pruning.

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Section: Introductionmentioning

confidence: 53%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

Deivasigamani

Miteva

Natale

et al. 2021

Preprint

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“…These abnormal neuronal connections caused a decrease in social interaction with the mother at the age of 60 days [ 86 ]. Yilmaz et al generated mice overexpressing human C4A with a knockout of the murine C4 gene [ 87 ]. These mice exhibited enhanced microglial synaptic pruning in the PFC and a reduction in spine density at 60 days of age [ 87 ].…”

Section: Microglia–synapse Interaction In Schizophreniamentioning

confidence: 99%

New Insights Regarding Diagnosis and Medication for Schizophrenia Based on Neuronal Synapse–Microglia Interaction

Izuo

Nitta

2021

JPM

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Schizophrenia is a common psychiatric disorder that usually develops during adolescence and young adulthood. Since genetic and environmental factors are involved in the disease, the molecular status of the pathology of schizophrenia differs across patients. Recent genetic studies have focused on the association between schizophrenia and the immune system, especially microglia–synapse interactions. Microglia physiologically eliminate unnecessary synapses during the developmental period. The overactivation of synaptic pruning by microglia is involved in the pathology of brain disease. This paper focuses on the synaptic pruning function and its molecular machinery and introduces the hypothesis that excessive synaptic pruning plays a role in the development of schizophrenia. Finally, we suggest a strategy for diagnosis and medication based on modulation of the interaction between microglia and synapses. This review provides updated information on the involvement of the immune system in schizophrenia and proposes novel insights regarding diagnostic and therapeutic strategies for this disease.

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Synaptic Density in Early Stages of Psychosis and Clinical High Risk

Blasco,

Nisha Aji,

Ramos-Jiménez

et al. 2024

JAMA Psychiatry

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ImportanceSynaptic dysfunction is involved in schizophrenia pathophysiology. However, whether in vivo synaptic density is reduced in early stages of psychosis, including its high-risk states, remains unclear.ObjectiveTo investigate whether synaptic density (synaptic vesicle glycoprotein 2A [SV2A] binding potential) is reduced in first-episode psychosis (FEP) and in clinical high risk (CHR) and investigate the effect of cannabis use on synaptic density and examine its relationship with psychotic symptoms and gray matter microstructure across groups.Design, Setting, and ParticipantsThis cross-sectional study was performed in a tertiary care psychiatric hospital from July 2021 to October 2023. Participants were patients with antipsychotic-free or minimally exposed FEP or CHR and healthy controls with a clean urine drug screen (except cannabis).Main Outcomes and MeasuresSynaptic density was quantified with dynamic 90-minute [18F]SynVesT-1 positron emission tomography (PET) scans across prioritized brain regions of interest (ROIs) delineated in individual magnetic resonance images (MRIs). Cannabis use was confirmed with urine drug screens. Gray matter microstructure was assessed using diffusion-weighted MRI to estimate neurite density.ResultsA total of 49 participants were included, including 16 patients with FEP (mean [SD] age, 26.1 [4.6] years; 9 males and 7 females), 17 patients at CHR (mean [SD] age, 21.2 [3.5] years; 8 males and 9 females), and 16 healthy controls (mean [SD] age, 23.4 [3.6] years; 7 males and 9 females). Synaptic density was significantly different between groups (F2,273 = 4.02, P = .02, Cohen F = 0.17; ROI: F5,273 = 360.18, P &lt; .01, Cohen F = 2.55) with a group × ROI interaction (F10,273 = 2.67, P &lt; .01, Cohen F = 0.32). Synaptic density was lower in cannabis users (F1,272 = 5.31, P = .02, Cohen F = 0.14). Lower synaptic density across groups was associated with more negative symptoms (Positive and Negative Syndrome Scale negative scores: F1,81 = 4.31, P = .04, Cohen F = 0.23; Scale of Psychosis-Risk Symptoms negative scores: F1,90 = 4.12, P = .04, Cohen F = 0.21). SV2A binding potential was significantly associated with neurite density index (F1,138 = 6.76, P = .01, Cohen F = 0.22).Conclusions and RelevanceThis study found that synaptic density reductions were present during the early stages of psychosis and its risk states and associated with negative symptoms. The implications of SV2A for negative symptoms in psychosis and CHR warrant further investigation. Future studies should investigate the impact of cannabis use on synaptic density in CHR longitudinally.

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Overexpression of schizophrenia susceptibility factor human complement C4A promotes excessive synaptic loss and behavioral changes in mice

Cited by 216 publications

References 54 publications

Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

New Insights Regarding Diagnosis and Medication for Schizophrenia Based on Neuronal Synapse–Microglia Interaction

Synaptic Density in Early Stages of Psychosis and Clinical High Risk

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